Download - Base Excision Repair and Cancer

Mini-review

Base excision repair and cancer

Susan S. Wallace a,⇑, Drew L. Murphy b, Joann B. Sweasy a,b,1

aDepartment of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, University of Vermont, Stafford Hall, 95 Carrigan Drive, Burlington,

VT 05405-0068, United StatesbDepartment of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, HRT 313D New Haven, CT 06510, United States

a r t i c l e i n f o

Article history:

Received 22 November 2011

Received in revised form 20 December 2011

Accepted 24 December 2011

Available online xxxx

Keywords:

Base excision repair

Cancer variants

a b s t r a c t

Base excision repair is the system used from bacteria to man to remove the tens of thousands of endog-

enous DNA damages produced daily in each human cell. Base excision repair is required for normal mam-

malian development and defects have been associated with neurological disorders and cancer. In this

paper we provide an overview of short patch base excision repair in humans and summarize current

knowledge of defects in base excision repair in mouse models and functional studies on short patch base

excision repair germ line polymorphisms and their relationship to cancer. The biallelic germ line muta-

tions that result in MUTYH-associated colon cancer are also discussed.

Ó 2012 Elsevier Ireland Ltd. All rights reserved.

1. Overview of the base excision repair pathway

Base excision repair (BER) repairs the majority of endogenous

DNA damages including deaminations, depurinations, alkylations

and a plethora of oxidative damages, a total of about 30,000 per

human cell per day [1]. BER is a highly conserved system from bac-

teria to humans (for reviews see [2–8]) and is characterized by five

distinct enzymatic reactions (for reviews see [3,9–11]) (Fig. 1). The

first step in BER is recognition and removal of an altered base by a

DNA glycosylase that cleaves the N-glycosyl bond releasing the

damaged base. If the enzyme is monofunctional, an abasic site

results, which is subsequently recognized and cleaved by an apu-

rinic endonuclease (APE1) which leaves 30 OH and 50 deoxyribose

phosphate (50dRP) termini (for a review see [12]). The 50dRP at

the nick is removed by the lyase activity of DNA polymerase b

(Pol b) [13,14]. If the glycosylase is bifunctional, its associated lyase

activity cleaves the DNA backbone and leaves either an a,b-unsat-urated aldehyde (PUA) or a phosphate group attached to the 30 end

of the break [15,16]. a,b unsaturated aldehydes are removed by the

diesterase activity of APE1 to create a 30 hydroxyl substrate for Pol

b [17]. If a phosphate group is left on the 30 end, it is removed by

the phosphatase activity of polynucleotide kinase (PNKP) [18]. In

short patch BER, also known as single nucleotide BER, DNA Pol b in-

serts the missing base [19,20] with the resulting nick sealed by

DNA ligase III complexed to XRCC1 (for a review see [21]). XRCC1

is a non-enzymatic scaffold protein for BER [22] and has been

shown to interact with a number of the BER proteins [23–25].

In long patch BER, a polymerase (b,d,e) fills in the one base gap

and keeps synthesizing DNA while displacing the DNA down-

stream of the initial damage site, creating a flap of DNA. Pol b

has been shown to be necessary for this step and possesses strand

displacement synthesis activity [26]. FEN1 then removes this flap

from the DNA, leaving behind a nick in the DNA [27] and 2–13

nucleotides are removed from the original site of damage. The

choice of whether repair is accomplished via short or long patch

BER mainly depends on whether the abasic sugar is oxidized or re-

duced, as Pol b cannot eliminate a modified sugar [28]. If the 50 su-

gar is modified, it is not removed by Pol b and long patch BER is

initiated [28–31]. After initial strand displacement synthesis by

Pol b, several additional nucleotides are added. It has also been

shown that XRCC1 and LigIIIa may play a role in switching

between short and long patch BER [32,33]. Under conditions of

low ATP concentration, strand displacement synthesis by Pol b

can be stimulated by XRCC1/LigIIIa. In addition, there is extensive

evidence in mammalian cells that the BER enzymes interact with

each other as well as other proteins that promote recruitment of

downstream BER components and coordination of the BER process

(for a review see [34]).

This review will focus on short patch BER with emphasis on

mouse models and human germ line and tumor variants. The role

of polymorphisms in DNA BER genes in disease susceptibility has

recently been discussed in a number of excellent reviews (for

example see [35–44]).

0304-3835/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/j.canlet.2011.12.038

⇑ Corresponding author. Tel.: +1 802 656 2164; fax: +1 802 656 8749.

E-mail addresses: [email protected] (S.S. Wallace), joann.sweasy@yale.

edu (J.B. Sweasy).1 Tel.: +1 203 737 2626; fax: +1 203 785 6309.

Cancer Letters xxx (2012) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Cancer Letters

journal homepage: www.elsevier .com/locate /canlet

Please cite this article in press as: S.S. Wallace et al., Base excision repair and cancer, Cancer Lett. (2012), doi:10.1016/j.canlet.2011.12.038

2. The uracil/thymine processing glycosylases: UNG, SMUG, TDG

and MBD4

Uracil arises in DNA from misincorporation of dUMP from the

nucleotide pools and by deamination of DNA cytosine; mispaired

thymine is formed by deamination of methylcytosine. The deami-

nation products are highly mutagenic since they would now pair

with A instead of G. In fact, the first BER enzyme discovered by To-

mas Lindahl some 35 years ago was Escherichia coli uracil glycosy-

lase, the enzyme that removes deaminated cytosines and

misincorporated uracils from DNA [2]. In humans (for reviews

see [45,46]), the UNG gene encodes a nuclear version of uracil gly-

cosylase, UNG2, whose primary role is to remove misincorporated

uracils [47–49], and a mitochondrial version, UNG1. In addition,

UNG2, as well as a second uracil glycosylase, SMUG1, excises ura-

cils that arise from deamination of cytosine [49,50]. SMUG1 can

also remove 5-hydroxymethyluracil from DNA [51]. UNG2 also

plays a major role in somatic hypermutation and class switch

recombination [52]. Both UNG1 and SMUG1 are members of the

UDG superfamily which have similar structural motifs [53–55].

The structure of SMUG1 shows it to have a more invasive interac-

tion with the DNA duplex disrupting more than one base pair [56].

Humans contain two mismatch DNA glycosylases, TDG and

MBD4, that remove thymines from thymine:guanine mismatches

arising from deamination of methyl cytosine. TDG has a strong

preference for uracil over thymine and MBD4 removes uracil and

thymine resulting from deamination of CpG and methylated CpG,

respectively [57]. TDG is also a member of the UDG superfamily

[55]. The crystal structure of human TDG has been recently solved

[58–60]. Interestingly, unlike its bacterial homologs, human TDG

contains an insertion loop that contributes to its CpG sequence

specificity [60]. TDG has recently been implicated in the active

demethylation process that takes place during development [61].

5-Methylcytosine (5-meC) can be converted to 5-hydroxymethyl-

cytosine (5-OHmeC) by the ten eleven translocation (Tet) family

of dioxygenases. 5-meC and 5-OHmeC can be further oxidized to

5-carboxylcytosine by TET and recognized and removed by TDG

[61,62]. MBD4, also called MED1, contains two domains, one that

recognizes methylated and hemimethylated CpG and the other

that contains glycosylase activity that removes G mispaired with

T. The glycosylase domain of MBD4 is homologous to the helix-

hairpin-helix (HhH) superfamily of DNA glycosylases [57,63]. The

methyl-CpG binding domain consists of a compact a/b fold with

an extended loop between two anti-parallel b strands that inserts

into the major groove containing methyl-CpG sequences confer-

ring specificity [64,65]. MBD4 has also been suggested to play a

role in active demethylation. In this case an AID deaminase con-

verts 5-MeC to thymine which is then removed by MBD4 or TDG

(for a review see [66]). All of the glycosylases in the UDG superfam-

ily are monofunctional.

Fig. 1. Short patch base excision repair.

2 S.S. Wallace et al. / Cancer Letters xxx (2012) xxx–xxx


2.1. Mouse models for the uracil/thymine processing glycosylases

For the most part mice nullizygous for a single glycosylase ex-

hibit very few phenotypes which is in contrast to the severe phe-

notypes associated with the enzymes downstream from the DNA

glycosylases (for reviews see [67,68]). Many of the DNA glycosy-

lases exhibit broad and/or overlapping substrate specificities and

thus can compensate for one another. For example, Ung deficient

mice exhibit a mild increase in spontaneous mutation frequency

[48] which is in keeping with the presence of a second major uracil

DNA glycosylase, Smug1. In Ungÿ/ÿ mice there was a 1000-fold in-

crease in DNA uracil compared to wild type probably due to incor-

poration of dUMP which pairs correctly [48]. Ung deficient mice

also display an increased incidence of spontaneous B cell lympho-

mas during old age consistent with the role of Ung in somatic

hypermutation and class switch recombination [69]. In keeping

with this, a deficiency of human UNG is associated with impaired

class-switch recombination [52]. Mbd4ÿ/ÿ mice generated by a tar-

geted allele replacement were viable and fertile but exhibited an

increase of C? T transitions at CpG sites [70]. When crossed with

cancer-prone Apc heterozygotes, the Mbd4ÿ/ÿ mice showed accel-

erated tumor production with CpG? TpC mutations in Apc [70].

A recent study has found that, unlike mice nullizygous for other

DNA glycosylases, nullizygous Tdgÿ/ÿ mice are embryonic lethal

which is apparently associated with an epigenetic defect that af-

fects expression of developmental genes [71]. Tdg appears to initi-

ate BER in response to aberrant de novo methylation [71].

2.2. Polymorphisms in the UNG superfamily and cancer

To date there have only been two UNG gene mutations that have

been associated with cancer. The first, UNG Arg88Cys, is a

polymorphism that was found in the germline of a family with

colorectal cancer [72], and the second, an UNG Gly143Arg muta-

tion, was found in a sporadic glioblastoma [73]. A number of

sequence variants of UNG were studied in a variety of cell lines

but none showed a significant decrease in uracil glycosylase activ-

ity [74]. Gastric cancers were of particular interest in this study

since genetic instability has been observed in the region of UNG

(12q24.1) [75], but again no defect was observed [74]. Recently

germ line polymorphisms in SMUG1 were examined in over 1000

cases of breast cancer and 2000 cases of age and race matched

controls. Two polymorphisms in the SMUG1 promoter region were

found to moderately affect the risk of breast cancer in heterozy-

gotes carrying them [76]. Interestingly, the DNA in individuals

homozygous for these variants exhibit increased levels of uracil

[77].

The human thymine DNA glycosylase, TDG, maps at chromo-

some 12q22-q24.1 which is also associated with a high loss of het-

erozygosity in gastric cancers [75]. However, none of the tumor

samples analyzed showed a mutation in the coding sequence of

the remaining TDG allele [75]. Two other polymorphic variants of

TDG, G199S and V367M, were looked at with respect to lung can-

cer risk and no statistically significant associations were found

[78].

Frameshift mutations in MBD4 have been identified in Japanese

gastric cancers [79] and polymorphisms of the MBD4 gene have

also been linked to the risk for primary lung cancer and esophageal

squamous carcinoma in a Chinese population [80,81]. A recent

study showed that the Glu346Lys polymorphism was significantly

associated with the risk of colorectal cancer [82]. However, the

same study found no association between the frameshift muta-

tions in the MBD4 gene and gastric and colorectal cancers [82]. In

an Australian study of hyperplastic polyposis syndrome four

patients were found to be heterozygous for the MBD4 Ala273Thr

variant [83]. Interestingly, a study designed to predict survival

from non-small cell lung carcinoma found that combining SNPs

in six DNA repair genes including the MBD4 Glu346Lys variant,

provided significant prognostic markers for clinical outcome [84].

3. MPG: methylpurine DNA glycosylase

3-Methylpurine DNA glycosylase (MPG), also known as AAG

(alkyladenine DNA glycosylase), recognizes and removes a broad

spectrum of alkylated bases including not only 3-methyladenine

[85], but guanines methylated at the N3 or N7 position [86–89],

etheno adenine and guanine [90,91], hypoxanthine [92] and 8-oxo-

guanine [93] as well as other alkylated and oxidized DNA sub-

strates [94]. MPG/AAG is a monofunctional glycosylase. Although

humanMPG/AAG has a similar broad substrate specificity to bacte-

rial and yeast AlkA, they are not structurally related [95] with AlkA

being a member of the HhH superfamily that includes the glycosy-

lases NTH1 and OGG1. The MPG/AAG DNA glycosylase consists of a

single mixed a/b domain that is different from the other glycosy-

lases [95], but like AlkA, the active site is lined with aromatic ami-

no acids for binding to the electron-deficient alkylated bases that it

recognizes [95].

3.1. Mouse models for MPG/AAG

Two groups generated Mpg/Aag defective mice. In both cases

the mice were viable and developed normally with the cells being

moderately sensitive to alkylating agents and showing a significant

reduction in the repair of 3-MeA but not 7-MeG [96,97]. Also, the

Mpg/Aag-null mice, when treated with azoxymethane to induce

alkylation damage or dextran sulfate to induce inflammation exhi-

bit a higher frequency of colon cancer than similarly treated wild

type mice [98]. Mpg/Aag deficient mice also showmore severe gas-

tric lesions than wild type after infection with Helicobacter pylori

[99]. Interestingly, although most Mpg/Aag null cells are sensitive

to alkylating agents [97,100], myeloid cells from Aagÿ/ÿ mice are

more resistant [101]. It has been suggested that an imbalance of

BER enzymes can cause more damage once repair by MPG/AAG is

initiated because the resulting AP sites would be lethal if there

was not sufficient APE1 to continue the BER process [101,102].

3.2. MPG/AAG polymorphisms and cancer

Although most studies show no association between MPG/AAG

polymorphisms and cancer risk [72,103,104], one patient with lung

cancer had the MPG Arg55Cys polymorphism variant [105] and an-

other patient with osteosarcoma was heterozygous for a SNP up-

stream of MPG [106].

4. Repair processing of 8-oxoguanine: OGG1 and MUTYH

Guanine has the lowest redox potential of any base in DNA and

therefore it is readily oxidized to 8-oxoguanine. 8-Oxoguanine is

recognized and removed by OGG1 when it is paired with cytosine

[107–112]. OGG1 also removes FapyG and 8-oxoA from DNA [113–

116]. OGG1 is a member of the HhH family of DNA glycosylases

which contains an HhH motif followed by a GlyPro-rich loop and

a conserved aspartic acid which initiates a nucleophillic attack on

the epsilon amino group of a conserved lysine. It then attacks the

anmeric carbon and releases the free base. The Schiff base interme-

diate results in strand cleavage. Thus OGG1 is bifunctional. OGG1

has been crystallized, unliganded and bound to an 8-oxoG:C con-

taining DNA [117,118]. In addition to the two alpha-helical do-

mains common to all superfamily members, a third anti-parallel

beta sheet, which is found in E. coli AlkA is also found in OGG1.

OGG1 is not cycle regulated and apparently scans the DNA for its

S.S. Wallace et al. / Cancer Letters xxx (2012) xxx–xxx 3


oxidized purine substrates. If 8-oxoguanine (or FapyG) is encoun-

tered by a replication fork prior to repair, adenine is often inserted

opposite the lesion by the replicative polymerase [119,120]. DNA

glycosylase MUTYH can remove this adenine preventing mutation

fixation [121–127]. The structure of the E. coli homolog of MUTYH,

MutY, has been solved [128,129]. MUTYH is also a member of the

HhH superfamily, but in addition to the HhH binding motif, it con-

tains an iron sulfur cluster that is involved in DNA binding

[130,131]. MUTYH is a monofunctional enzyme. OGG1 is the only

human glycosylase that efficiently removes 8-oxoG from DNA

and MUTYH is the only glycosylase that removes A incorporated

opposite 8-oxoG, although the mismatch repair system is also able

to remove this adenine [132–134].

4.1. Mouse models

Mice deficient in OGG are viable and fertile [135,136] although

8-oxoG lesions accumulate in the liver but not in other organs

examined [137]. These increased levels are responsible for an ele-

vated spontaneous mutation rate [135,136]. Also, when exposed to

KBrO3 [138] or UVB [139], the Oggÿ/ÿ mice exhibited increased

damage, mutations, and in the case of UVB, skin tumors.

MutYÿ/ÿ mice are also viable and healthy [140] but they have

about a 2-fold increase in spontaneous mutation frequency in

embryonic stem cells [141]. Again, there is an accumulation of 8-

oxoG that seems to occur only in the liver [142]. In contrast to

the single knockout Ogg and MutY mice, Oggÿ/ÿMyhÿ/ÿ double

knockout mice exhibit a significantly increased tumor incidence

with a higher frequency of lymphomas, lung and ovarian tumors

compared to wild type and the single knockout mice [140].

4.2. OGG1 and MUTYH polymorphisms and cancer

The most common polymorphic variant of OGG1, Ser326Cys, is

observed at an average frequency in the population of approxi-

mately 32% and is the most well-studied variant of OGG1 (for re-

cent reviews see [143,144]). There have been at least 100

published studies on this variant, most with marginally significant

correlations with disease, and which will not be reviewed in detail

here. Earlier reviews of the epidemiologic studies suggested that

there was some evidence of risk for esophageal, lung, nasopharyn-

geal, oroplaryngeal and prostate cancer related to the Ser326Cys

polymorphism, but risk of breast cancer was not found [143,145–

147]. There also appeared to be no risk of colon cancer associated

with this variant [148]. A more recent meta-analysis [144] of OGG1

Ser326Cys and lung cancer risk concluded that individuals with the

Cys/Cys genotype did not have a significantly increased risk of lung

cancer compared to the Ser/Ser genotype. However, when the

Asian population was separated out there did appear to be an in-

creased risk for lung cancer among non-smokers with Cys/Cys

and Ser/Cys genotypes compared to Ser/Ser [144], although others

found an association with smokers [149]. The Cys/Cys genotype

has also been shown to increase the risk of childhood leukemia

[150] and renal cell carcinoma [151]. In addition, functional varia-

tions in the 50UTR of OGG1 have been associated with an increased

risk of breast cancer [152].

There have been a number of functional studies on the

Ser326Cys variant. It does not have a major catalytic defect having

a kcat about 63% of wild type [153]. Other studies also showed the

activity of the Ser325Cys variant to be less than that of the wild

type protein [154,155]. In lymphocytes, the efficiency of removal

of 8-oxoG by the variant was also similar to that of the wild type

enzyme [156]. Several groups measured the ability of the OGG1

Ser326Cys variant to complement the high spontaneous mutation

frequency observed in E. coli fpg mutYmutants. One group found no

difference between the wild type and the variant in the ability to

complement the phenotype [154] while another found the variant

less able to suppress spontaneous mutagenesis in E. coli [157], and

a third found the Ser326Cys variant less efficient in the repair of a

plasmid containing 8-oxoG using a SupF forward mutation assay in

human cells [158]. The Ser326Cys variant was shown to exhibit

aberrant DNA binding probably involving dimerization [159] while

oxidation of the Cys in the variant was shown to alter its repair

competence [160,161]. It has also been suggested that the Cys sub-

stitution affects the nuclear localization of OGG1, possibly by alter-

ing its phosphorylation status [162].

The OGG1 Ile321Thr polymorphic variant was also found in the

germline of one patient with colorectal adenomas and not in nor-

mal controls [163]. Two OGG1 polymorphic variants, Thr398Ser

and Ser31Pro were observed in primary sclerosing cholangitis pa-

tients [164]. However, the Ser31Pro variant was found to have gly-

cosylase and DNA binding activity similar to wild type [163,164].

In cancer cells, the OGG1 Arg154His mutation has been de-

tected in one out of nine gastric cancer cell lines, Arg131Gln has

been found in one out of forty human tumors, and Arg46Gln has

been found in lung and renal tumors. All three of these have re-

duced glycosylase function [153,154,157,165,166].

In 2002 a British family was diagnosed with multiple colorectal

adenomas and carcinomas but the family members lacked the

inherited adenomatous polyposis coli (APC) gene defect ([167]

and for reviews see [168–170]). When these investigators exam-

ined the tumors they found a high proportion of GC? TA transver-

sions in the APC gene [167], a signature of a defect in MUTYH (and

OGG1), which removes adenine misincorporated opposite 8-oxo-

guanine or FapyG. It turns out that these patients have biallelic

mutations in MUTYH and are predisposed to MUTYH-associated

polyposis (MAP) [171]. MAP transmission occurs as an autosomal

recessive trait with very high penetrance although the phenotype

of MAP patients is closer to the attenuated form of the classic

familial adenomatous polyposis, rather than the severe form

[170]. Interestingly, most of the G? T transversions observed in

APC were at GAA sequences [167,172]. The APC gene contains

216 of these sequences where G? T transversions would lead to

a truncated protein making it a particularly vulnerable target. In

addition to mutations in the APC gene, individuals with serrated

polyps had GC? TA transversions in KRAS in these polyps [173].

Although colorectal cancers predominate in MAP patients, a recent

multicenter European study reported an excess of ovarian, bladder,

and skin cancers with a trend towards an increased risk of breast

cancers [174].

There are at least 30 mutations in the MUTYH gene that are pre-

dicted to truncate the protein including nonsense, small insertions

and deletions and splice site variants. There are also well over 50

missense mutations of which over 30 have been observed in indi-

viduals with MAP. The most common missense variants found in

MAP patients (about 70%) are Ty165Cys and Gly382Asp (for loca-

tions of these variants see [168,169]). Interestingly, the Bacillus ste-

arothermophilus Tyr88 corresponding to Tyr165 in MUTYH, is a

wedge residue that intercalates 50 to the 8-oxoG in the DNA mole-

cule and participates in the extrusion of the adenine into the active

site pocket [129]. This residue corresponds to the phenylalanine

wedge amino acid in bacterial formamidopyrimidine DNA glycosy-

lases (Fpg) that crystallographic studies have suggested interca-

lates adjacent to cytosine opposite the 8-oxoG and senses the

differences in sugar pucker between 8-oxoG and G [175]. The same

phenylalanine residue in Fpg has been shown in single molecule

experiments to probe DNA for the lesion [176].

A number of assays have been used to assess the activity of the

MUTYH variants (Table 1) including substrate binding and glycosy-

lase assays [164,177–185] as well as the ability of the variants to

complement the spontaneous mutation frequency of E. coli mutY

mutants [177,180,182]. Using these assays, the human MUTYH



variant, Tyr165Cys, was found to have little or no substrate binding

[177,181,183] or glycosylase activity [182–185] and a greatly re-

duced ability to complement the increased spontaneous mutation

frequency exhibited in E. coli mutY mutants [177,182]. Recently,

the effect of expression of MUTYH variants in MutYÿ/ÿ mouse em-

bryo fibroblasts on hypersensitivity to various stressors has been

used to assess function and both the Tyr165Cys and Gly382Asp

variants had severe defects [185].

The Gly382Asp variant is present in the C-terminal domain of

MUTYHwhich shares homology with MutT. MutT hydrolyzes 8-ox-

odGTP into 8-oxodGMP thereby preventing its incorporation into

DNA [186–188]. In MUTYH this domain has been shown to be

important for 8-oxoG recognition [129,189,190]. When the corre-

sponding E. coli MutY Gly253Asp variant was examined, it showed

a loss of affinity to duplexes that had 8-oxoG rather than G which

was similar to results observed with E. coli MutY that was trun-

cated for the C-terminal domain [177]. The Gly253Asp variant of

E. coli MutY also showed an 85% reduction in glycosylase activity

and failed to complement the mutY mutator phenotype of E. coli

[141]. In single turnover experiments the MUTYH Gly382Asp var-

iant exhibited about 30–40% the activity of wild type and was able

to partially suppress the spontaneous mutation frequency ob-

served in E. coli mutants [182]. Other studies showed glycosylase

levels to range from 15% to 50% [182–185] of wild type levels. In

keeping with the in vitro studies, it was reported that MAP patients

with homozygous Gly382Asp mutations and heterozygous

Tyr165Cys/Gly382Asp mutations had a milder phenotype than

homozygous Tyr165Cys patients [191].

A number of other MUTYH variants have been recently charac-

terized (Table 1) and many were shown to have reduced 8-oxoG:A

binding and glycosylase activity as well as a substantially reduced

ability to suppress the spontaneous mutation frequency of E. coli

mutY mutants. Thus there has been substantial progress in under-

standing which variants are nonpathogenic polymorphisms that

are only coincidently found in patients with MAP and which poly-

morphisms are functional. Also, several recent studies found a

clear increase in colon cancer incidence in individuals with only

a single germline MUTYH mutation [192–195].

5. Recognition of oxidized pyrimidines: NTH1, NEIL1, NEIL2 and

NEIL3

There are four human DNA glycosylases that recognize oxidized

pyrimidines and formamidopyrimidines and all are bifunctional.

Human NTH1 appears to be a housekeeping DNA glycosylase that

scans the DNA for these damages [115,196–200]. NTH1, like

OGG1 and MUTYH, is also a member of the HhH superfamily

[201], and like MUTYH, also contains an iron sulfur cluster [201].

NTH1 recognizes a fairly broad spectrum of oxidized pyrimidines.

In contrast to NTH1, the NEIL proteins appear to have special-

ized functions. NEIL1 is cell cycle regulated [202] and because

NEIL1 binds to a number of replication proteins, it may be associ-

ated with the replication fork [18,203–205]. NEIL1 recognizes oxi-

dized pyrimidines, formamidopyrimidines (FapyG and FapyA)

[202,206–216], spiroiminodihydantoin (SP) and guanidinohydan-

toin (Gh) [217,218]. The crystal structure of NEIL1 has been solved

and is structurally related to its bacterial homologs although it

contains a ‘‘zincless’’ finger used for binding rather than the proto-

typic family zinc finger [219]. NEIL2 recognizes the same lesions as

NEIL1 but prefers them in single-stranded DNA [220,221]. Recent

evidence showing that NEIL2 binds to RNA polymerase II and other

transcription-associated proteins, suggests that NEIL2 may be

associated with transcription [222]. NEIL3 has the same substrate

specificity as NEIL2 [223] and in humans is found in the thymus

and testis [224]. NEIL1 and 2 have a b/d AP lyase activity which

Table 1

Characterized MUTYH variants found in MAP patients.a

Variant Glycosylase activity Substrate binding Complementation of E. coli mutY

spontaneous mutation frequency

V22M WT [181] WT [181]

V61E WT [184]

R83X No activity [184]

Y90X No activity [181] No binding [181]

I103delC No activity [181] No binding [181]

137insIW 35% [185], 40% [183] Slight decrease [183]

Y165C No activity [185,183], severe defect [181], 4.5% [184] 30–40% [182] Greatly reduced [181,183,177] No [182,177]

R168H No activity [184]

R171W No activity [185,183] Greatly reduced [183]

I209V 66.9% [184]

D222N No activity [184]

R227W Severe defect [179] Greatly reduced [179]

R231H Severe defect [181] Severe defect [181]

R231L Severe defect [180] Severe defect [180] No [180]

V232F Partial activity [179] Partial binding [179]

R260Q Reduced [181], severe defect [164] Reduced [181]

M269V 10.7% [184]

P281L Severe defect [181] Greatly reduced [181]

R295C WT [184]

Q324H Reduced [181]

Q324R No activity [184] 30–40% [182] WT [182]

A359V WT [184]

L374P No activity [184]

Q377X No activity [181] No binding [181]

G382D 15.2% [184], 30–40% [182], 50% [183], Reduced [181], WT [185] Greatly reduced [177] reduced [181,183] Partial [182]

P391L No activity [184] 30–40% [182] No [182]

H434D WT [164]

A459D Severe defect [178]

E466del No activity [181,184,185,183] No binding [181] greatly reduced [183]

S501F WT [184]

a The MUTYH variant amino acid numbers used in this table follow the original notation (see [168,169]). However, the MUTYH variants used in [181] are the mitochondrial

form which is ÿ14aa from that used here. Also, the most up-to-date annotation uses the full length protein +14aa from the notation used here [174].



leaves a phosphate attached to the 30 side of the nick while NEIL3

has poor AP lyase activity that primarily cleaves the DNA backbone

by b-elimination [223,225].

5.1. Mouse models for NTH and the NEIL glycosylases

Nullizygous mice have been generated for Nth1 [226,227], Neil1

[228] and Neil3 [209,224]. Mice are viable, fertile and resemble

wild type mice during the early stages of life [67] but most showed

an increase in base lesions in the genomic DNA of targeted organs

[226,229]. A number of the NEIL1 knockout mice, primarily males,

developed symptoms of fatty liver disease and obesity similar to

that of human metabolic syndrome [228]. These symptoms were

attributed to accumulation of unrepaired damages in mitochon-

drial DNA. More recent studies have demonstrated that the Neil1

mice are more susceptible to obesity because of lower tolerance

for oxidative stress [230]. Although, with the exception of Neil1,

there are no obvious phenotypes in nullizygous mice lacking a sin-

gle oxidative DNA glycosylase, double knockout mice are tumor

prone. Nthÿ/ÿ Neil1ÿ/ÿ mice exhibit lung and liver tumors with a

higher frequency compared to the single knockout mice [231].

5.2. Polymorphisms in NEIL1, NEIL2 and NEIL3 and cancer

There are a number of polymorphic variants of NEIL1, NEIL2 and

NEIL3 in the SNP databases (see for example [44]). The Gly83Asp

NEIL1 polymorphic variant has been found in two patients with

cholagiocarcinoma [164]. The Gly83Asp variant shows reduced

base excision activity on double stranded DNA with altered AP

lyase activity [164,232]. However, this variant was able to remove

bases from single stranded DNA with wild type efficiency [164]. A

NEIL1 Glu181Lys variant was also observed in a patient with pri-

mary sclerosing cholangitis but the protein was insoluble upon

expression in bacteria [164]. Two rare NEIL1 variants, Pro208Ser

and Arg339Gln, were found in patients with colorectal adenomas

but the Arg339Gln variant was also found in a normal control

[163]. Neither of these variants was characterized functionally.

Three other variants of NEIL1 found in the SNP databases have

been characterized with Ser82Cys and Asp252Asn exhibiting wild

type activity, while Cys136Arg showed both reduced glycosylase

and AP lyase activity [232].

Two NEIL1 variants, Lys242Arg and Gly245Arg, were identified

in gastric tumors in Chinese patients and another NEIL1 variant,

Arg334Gly, was identified in a Japanese patient [233]. These vari-

ants all behaved like wild type NEIL1 in an activity assay [233]. A

NEIL1 deletion mutant, Gly28Del, that results in a truncated pro-

tein and a NEIL1 splicing mutation have also been found in gastric

cancers. The Gly23del variant had little to no activity while the

truncated protein from the splicing variant lost its nuclear localiza-

tion signal [233]. Three novel NEIL1 promoter polymorphisms

were also found in patients with gastric cancer [234].

Three polymorphic variants of NEIL2, Arg103Gln, Pro123Thr

and Arg257Leu, were identified in patients with family histories

of colorectal cancer and were not observed in controls [72]. The

NEIL2 Arg103Gln and Arg257Leu variants were also found in

patients with multiple colorectal carcinomas but were also found

in controls [163]. An additional NEIL2 variant, Arg164Thr, was

found in a single patient and not in the control population [163].

Ten variants of NEIL3 were found in patients with multiple colorec-

tal adenomas, but only one of these, Glu132Val, was present in a

patient but not in a control population [163]. The NEIL2 and NEIL3

variants have not been evaluated for function. Finally, although

there are a number of NTH1 polymorphic variants identified in

the databases (and see [44]), as of yet none have been associated

with disease.

6. AP endonuclease, APE1 (also called APEX1, REF1)

There are two genes encoding AP endonucleases in humans.

APEX1 encodes the principal enzyme, APE1, that has both AP endo-

nuclease and 30 phosphodiesterase activity (for a review see [235]).

APE1 also contains redox-enhancing factor I (REF1) which reduc-

tively activates a number of transcription factors [236,237]. APE1

cleaves an AP site generated by a monofunctional DNA glycosylase

and leaves a 30 hydroxyl and a 50 deoxyribose [238–240]. APE1 is

the major enzyme in humans responsible for this activity. The dies-

terase activity of APE1 also removes the a,b-unsaturated aldehyde

left on the 30 side of the nick produced by the lyase activity of NTH1

and OGG1 [17]. The structure of APE1 shows it to have a four-lay-

ered a,b-sandwich fold characteristic of this family of proteins and

contacts the DNA in the minor groove [241]. There is a second APE1

gene that encodes human APE2. APE2 has 30 phosphodiesterase

activity and in addition has a 3–50 exonuclease activity that sup-

ports removal of mismatched nucleotides from the 30 end of the

nick [242–244]. APE2 has a very weak AP endonuclease activity

but efficient 30 phosphodiesterase activity [244,245]. Recent data

suggest that APE2 is involved in maintaining and regenerating B

cell precursor pools [246].

6.1. Mouse models for APE1 and APE2

Mice nullizygous for APE1 suffer early embryonic lethality

[247–249]. Nullizygous Ape1ÿ/ÿ mouse embryonic fibroblasts

(MEFs) [250] containing a human APE1 gene under CRE control

were used to distinguish between the AP endonuclease activity

of APE1 from the redox regulatory function of APE1. When hAPE1

was removed from these cells, apoptosis ensued and could only be

restored by complementing with both functions showing that both

are essential for cell viability. In contrast, in RNA knockdown

experiments with human cells, apoptosis was prevented by

expression of an unrelated AP endonuclease suggesting that it

was only AP endonuclease that was required for viability [251].

APE1 heterozygous mice are viable with no abnormal phenotype

compared to wild type mice [252]; however, APE1 heterozygotes

exhibit a higher spontaneous mutation frequency in spleen and

liver [252], sensitivity to oxidative stress [249] and lower BER

activity in liver and brain [253]. Mice nullizygous for APE2 appear

to develop normally but exhibit defects in lymphopoiesis support-

ing the idea that APE2 repairs DNA damage during lymphoid

development [246].

6.2. APE1 polymorphisms and cancer

The APEX1 gene that encodes APE1 maps to chromosome

14q11.2-q12. A number of polymorphisms have been identified

in the APEX1 gene, but the most common polymorphic variant is

Asp148Glu, present at about 46% of the population. Like the

Ser326Cys variant in OGG1, this common variant has also been

extensively studied resulting in over 50 publications which will

not be completely reviewed here. A number of studies have sug-

gested associations between the Asp148Glu variant and various

types of cancer. For example, one study showed it to predict cancer

risk for bladder cancer [254], but another showed it to be associ-

ated with a decreased risk for bladder cancer [255]. Similarly,

one study showed individuals with the Asp148Glu polymorphism

to have an increased risk of lung cancer [256] while other studies

showed carriers of the Asp148Glu polymorphism to have no in-

creased risk [36,257]. Asp148Glu was also shown to predict risk

for prostate cancer [258] and gastric cancer [259]. There has also

been a study suggesting that Asp148Glu conferred a risk for breast

cancer [260] while genome-wide association studies discounted



this [36,261–264]. One meta-analysis showed a moderately in-

creased risk for all cancer types for individuals with the Asp148Glu

polymorphism [265], while others found no increase [36].

The Asp148Glu variant protein, as well as other variants such as

Gly241Arg and Gly306Ala, have been biochemically characterized

and display essentially normal AP endonuclease and DNA binding

activities [266,267]. The Leu104Arg, Glu126Asp and Arg237Ala

exhibit 40–60% reduction in AP endonuclease activity while the

Asp283Gly variant exhibits only 10% of the repair capacity of the

wild type APE1 [266]. Two of the APE1 polymorphic variants,

Gln51His and Ile64Val are in the N-terminal region of the protein

not in the catalytic domain.

Mutations in APE1, Pro12Leu and Arg237Cys and one with a

premature stop codon, have also been found in three out of 20

endometrial tumors [268]. Arg237Cys behaves similarly to the

Arg237Ala having a substantially reduced AP endonuclease activity

[266].

7. DNA polymerase beta (Pol b)

Pol b is the main polymerase involved in BER, and is responsible

for two key activities in the BER pathway: DNA polymerase and dRP

lyase activities. Pol b is a small (39kD) polymerase, which unlike

replicative polymerases delta and epsilon, does not possess any

proofreading exonuclease activity. This leads to Pol b being a rela-

tively error prone polymerase, misincorporating the wrong nucleo-

tide in about one of every 10,000 nucleotide insertion events [269].

Pol b consists of two main domains, 8 kD and 31 kD, each

responsible for one of the activities of the polymerase [270,271].

The 31 kD domain possesses three subdomains named for their

structural correlation to a hand: thumb, palm, and fingers. The

thumb subdomain connects to the 8 kD domain and is the main

center for DNA binding by the polymerase as it contains two

HhH motifs. The palm domain contains the polymerase active site

residues: Asps 190, 192, and 256 [272]. The palm domain is con-

nected to the fingers domain through a flexible hydrophobic hinge

region. The fingers domain of the polymerase is responsible for

nucleotide binding and selection. The 8 kD domain houses the

deoxyribose phosphate (dRP) lyase activity.

The polymerization mechanism of Pol b consists of four basic

steps. First, Pol b binds to one base gapped DNA to form a polymer-

ase-DNA binary complex. This binary complex next binds nucleo-

tide, forming an enzyme–DNA–dNTP ternary complex. Once

dNTP is bound in the active site, there is a rapid conformational

change wherein the fingers domain rotates through the hydropho-

bic hinge region to close around the nucleotide. This movement

initiates the nucleotidyl transferase activity in the active site, add-

ing the nucleotide to the DNA strand. Lastly, in a likely rate-limit-

ing step, the DNA product extended by one nucleotide is released

from the polymerase generating an apo-enyzme that can complete

the cycle again [273].

One putative source of mutagenesis is the lack of removal of 8-

oxoG, which is a major product of oxidative base damage that is

usually repaired by BER. DNA polymerases, including Pol b, insert

A opposite this base if it is present in DNA. Unmodified G assumes

an anti conformation, but crystal structures show that this lesion

assumes a syn conformation that is consistent with efficient DNA

synthesis. This conformation is stabilized through Hoogsteen bond-

ing with the incoming adenine and a hydrogen bond with Asn279

[274]. Another underlying mechanism of mutagenesis is the inser-

tion of ribonucleotides into DNA. Pol b, like many other DNA poly-

merases, inserts ribonucleotides with an efficiency that is four

orders of magnitude less than that for dNTPs. Once incorporated,

Pol b can efficiently extend from the ribonucleotide. Pol b can insert

arabinofuranosylsytosine triphosphate (araC), but this is poorly

extended. For araC it is predicted that the O20 of araC would clash

with Asp276, but this does not seem to occur, suggesting that this

side chain can adjust to accommodate a hydroxyl at C20 [275].

Exclusion of the ribonucleotide does not occur via an amino acid

side chain as in other DNA polymerases, known as the steric gate,

but instead involves the backbone which in the case of Pol b is

Tyr271. This residue plays two significant roles. Its backbone car-

bonyl is unfavorably close to the 20-OH of the ribosewith little room

for adjustment. Tyr271 also binds to the minor groove edge of the

terminal primer base and the presence of a ribonucleotide obstructs

this interaction, which modulates active site geometry [276].

The Wilson laboratory has produced elegant high resolution

crystal structures of Pol b ternary complexes with mispairs in the

active site, using nonhydrolyzable analogs that were soaked into

the crystals. With a G–A mispair, the closed conformation is ob-

served and the mispaired bases are staggered. One hydrogen bond

is observed between the template and nascent bases. Staggered

bases, but no hydrogen bonds were observed for the C–A mispair.

To accommodate the staggered bases, the template strand shifts,

generating an abasic templating pocket. Interestingly R283 occu-

pies the space vacated by the templating nucleotide. The primer

terminus rotates as the complementary base is repositioned, which

moves the O30 of the primer terminus away from the alpha

phosphate, decreasing polymerase catalytic efficiency [277]. A

nonhydrolyzable A analog was soaked into crystals with a

tetrahydrofuran (THF) ‘‘template’’ and a closed conformation was

observed. However, the THF shifts upstream as in the structure

with the mispair and the primer terminus position is tenuous,

and likely not stable. Results suggest that R283 facilitates insertion

of A opposite the abasic site (THF) [278].

Additional evidence has recently shown that both the hydro-

phobic hinge and LoopII of Pol b are important for fidelity

[279,280]. Yamtich showed that alteration of Ile174 to Ser resulted

in an active polymerase that exhibited decreased fidelity for inser-

tion opposite template G. In the Ile174Ser variant the ground state

binding was altered, suggesting that the hinge is critical for the po-

sition and/or structure of the dNTP binding pocket [279]. Loop II is

a highly flexible loop that sits beneath the palm domain and alter-

ation of this loop leads to a decrease in the rate of DNA synthesis by

Pol b and in fidelity [280]. Interestingly, the Pro242Arg germline

variant of Pol b is present within Loop II [281].

7.1. Pol b mouse models

Like mice nullizygous for the other downstream BER enzymes,

Pol b null mice generated by the Cre-lox P system were not viable

[282] while another Pol b knockout survived embryonic develop-

ment but died from lung failure immediately after birth [283].

Pol b heterozygous mice exhibit higher levels of single strand

breaks (SSBs) and chromosomal aberrations than wild type [284],

as well as hypersensitivity to alkylating agents [284].

7.2. Germline and tumor-associated variants of Pol b

Variants in Pol b have been the topic of numerous reviews by our

group (see Nemec and references therein [43]). Genotyping of the

Pol b gene at 14 different sites along the gene has confirmed the

presence of two exonic germline variants, Arg137Gln and

Pro242Arg, in a few different global populations with minor allele

frequencies of nine and three percent, respectively [281]. This study

also revealed that there was a marked difference between haplo-

types in African versus non-African populations. The Arg137Gln

Pol b germline variant was shown to have lower DNA polymerase

activity than WT Pol b, was unable to complement Pol bD MEFs

for cellular sensitivity to alkylating agents, and was deficient in

BER reconstitution assays [285]. Little is known about the activity



of the Pro242Arg Pol b variant protein, but patients with lung can-

cer who carry this variant have decreased survival [286].

Approximately 30% of human tumors studied to date appear to

carry mutations in the Pol b gene that are not found in the germline

(for a review see [287]). Many of these mutations have functional

phenotypes that are associated with cancer, including deficient

polymerase or dRP lyase activity or they exhibit mutator activity

[288–291]. Pol b tumor-associated variants identified in lung, gas-

tric, colorectal, and prostate cancer induce cellular transformation

in immortalized epithelial cells [290,292] by inducing genomic

instability.

Pol b has also been shown to be overexpressed in a variety of

human tumors [293]. Overexpression in Chinese hamster ovary

cells has been shown to induce cellular transformation and geno-

mic instability [294,295]. Using a transgenic mouse model, Sobol

and colleagues demonstrated that overexpression of Pol b in cer-

tain organs, such as the stomach, resulted in hyperplasia [296].

Overexpression of Pol b can lead to imbalances in BER, which has

been shown in Saccharomyces cerevisiae to result in a mutator phe-

notype [297]. In human cells imbalances in BER proteins can result

in the accumulation of BER intermediates including single-strand

breaks (SSBs) and double strand breaks (DSBs) that lead to genomic

instability.

8. Ligase IIIa

Ligase IIIa (LigIIIa) seals the nick in the DNA backbone left after

Pol b fills in the gap and eliminates the dRP group. The LIGIII gene is

distinct from the other ligase genes (LIG1 and LIG4) in that there

are no homologs of LIGIII in lower eukaryotes [298]. There are three

forms of LigIII: a,b, and mitochondrial; all of which are encoded by

the same gene, another feature unique to LIGIII. LigIIIa interacts

tightly with XRCC1 via a BRCT domain at its C-terminus, and the

LigIIIa-XRCC1 complex is the major source of nick joining activity

in BER. LigIIIb lacks the C-terminal BRCT domain and is found only

in male germ cells where it is thought to function in meiotic

recombination. Mitochondrial LigIII (mtLigIII) possesses an N-ter-

minal mitochondrial localization signal in addition to the C-termi-

nal BRCT domain and functions in mitochondrial DNAmaintenance

in the absence of XRCC1. It has been shown that LigIII is phosphor-

ylated at Ser123 in replicating cells by Cdk2, a cell cycle kinase;

however, in response to oxidative DNA damage is dephosphoryl-

ated, and this is dependent upon ATM [298].

The nick-sealing ligase reaction is a three-step reaction that uti-

lizes the consumption of ATP. The consumption of ATP is required

to force the equilibrium of the ligase reaction to the right to avoid

the potentially disastrous reverse reaction where single SSBs are

induced in the DNA. LigIIIa attacks the ATP molecule through a cat-

alytic lysine residue (Lys421) [33], releasing pyrophosphate and

covalently linking AMP to the enzyme. Next, the AMP is transferred

to the 50-end of the DNA at the nick. Finally, the hydroxyl group at

the 30-end of the nick attacks the 50-phosphate on the 50-end,

expelling the once ligase-bound AMP and joining the two sides

of the nick together.

LigIIIa binds to the nicked DNA via its DNA binding domain.

This DNA binding is enhanced by the presence of the ZnF domain;

although, exactly how this stimulation is accomplished remains

unknown. Once bound to the DNA, LigIIIa curls in upon itself,

encircling the DNA. This allows for the DNA binding domain to

bend the DNA and unwind it, which exposes the nick on the oppo-

site side of the DNA to the catalytic domain. A consequence of the

need for LigIIIa to encircle the DNA substrate is that the complex of

LigIIIa-XRCC1 disrupts nucleosomes containing single nucleotide

gaps. As a result, the gap is more externally exposed for action

by Pol b, and thus, the activity of Pol b is stimulated on nucleo-

somes by the LigIIIa-XRCC1 complex [299].

8.1. LigIII nullizygous mice and human polymorphism variants

Like the rest of the downstream BER knockout mice, mice con-

taining a targeted knockout of LigIII are embryonic lethal [300]. In

mouse embryonic stem cells with a conditional allele of LigIII,

mitochondrial but not nuclear LigIII appears to be required for via-

bility [301]. Also, unlike XRCC1-deficient cells, LigIIIÿ null cells are

not sensitive to a number of DNA damaging agents [301]. In addi-

tion, although there are a number of LIGIII polymorphic variants

identified in the data bases (and see [44]) none have yet been asso-

ciated with a disease outcome.

9. X-ray cross complementing 1 (XRCC1)

XRCC1 acts as a scaffold during BER and single-strand break

repair (SSBR) repair and has no enzymatic activity of its own. XRCC1

interacts with several proteins that function in BER and SSB repair

including Pol b, PARP1, LigIIIa, APE1. For a recent comprehensive re-

view see [302]. It has recently been found that XRCC1 also functions

in an alternative nonhomologous end-joining pathway (alt-NHEJ),

which is microhomology-mediated [303]. XRCC1/LigIIIa interacts

constitutively with MRN/RAD50 in WT cells, but in cells deficient

in LigIV, the protein that acts in the major NHEJ pathway, signifi-

cantly less LigIIIa interacts with MRN. Rather, these proteins inter-

act specifically in the presence of DNA damage [304]. The NBS1 and

RAD50proteins interact directlywith both ligIIla and b. TheMRE11-

RAD50-NBS1 complex (MRN) stimulates intermolecular ligation of

compatible ends by LigIIIa and XRCC1 and also stimulates ligation

of incompatible ends using microhomology that is revealed by the

nuclease activity of MRE11 but in complex with RAD50 and NBS1.

New studies regarding functional interaction of XRCC1 with

several proteins are providing important insights into the critical

scaffolding role of XRCC1. For example, lack of interaction between

XRCC1 and polynucleotide kinase (PNKP) results in a remarkably

slow rate of SSBR. The 30 DNA phosphatase activity of PNKP is crit-

ical for rapid SSBR, which is facilitated by interaction with XRCC1.

The authors suggest that the interaction of PNKP with XRCC1 en-

sures that PNKP is not rate limiting during SSBR [305].

Recent studies have also suggested that XRCC1 functions at rep-

lication forks. XRCC1 is in complex in the cell with uracil DNA gly-

cosylase 2 (UNG2) and these proteins are colocalized with PCNA,

suggesting that they are at replication forks. This complex, isolated

from replicating cells, is able to function in the repair of DNA with

uracil residues. Interestingly, there is a reduced rate of repair of

uracils in XRCC1 deficient cells. UNG2 and XRCC1 colocalize specif-

ically in S-phase cells and therefore might catalyze a specialized re-

pair process in these cells [306]. The BRCT domain of XRCC1

interacts with the p58 subunit of DNA polymerase alpha-primase

(Pol b-primase) and XRCC1 and p58 colocalize in damaged cells.

P58 also interacts with polyADP ribose polymerase, which inhibits

its activity. Overexpression of the BRCT domain of XRCC1 in HeLa

cells increased PAR synthesis, which interferes with ongoing DNA

synthesis. The authors propose that inhibition of primase activity

by PAR is facilitated by interactions with XRCC1 and PARP-1 and

that this leads to fork slowing to allow for SSBR to be completed.

Thus, XRCC1 could play an important role in coordinating break re-

pair with replication [307].

Radicella previously demonstrated that XRCC1 interacts with

APE1 [308]. Recently it has been shown that APE1 interacts with

SIRTUIN1 (SIRT1), a protein deacetylase, and this interaction is in-

creased in response to genotoxic stress. SIRT1 deacetylates APE1.

Stress increases acetylation of SIRT1. Activation of SIRT 1 with



resveratrol stimulates binding of APE1 to XRCC1 and genotoxic

stress stimulates the binding of XRCC1 to APE1 which is sup-

pressed by knockdown or inhibition of SIRT1. Resveratol stimuates

AP endonuclease activity of the APE1–XRCC1 complex. Thus, SIRT1

may have a role in the regulation of BER by promoting association

of APE1 with XRCC1 [309].

9.1. XRCC1ÿ/ÿ mice

Mice nullizygous for XRCC1 die as early embryos [310]. XRCC1

heterozygous mice appear to develop normally but when treated

with an alkylating agent exhibit liver toxicity and an increase in pre-

cancerous colon lesions [311]. XRCC1ÿ/ÿ mouse embryo fibroblasts

and Chinese hamster ovary cells devoid of XRCC1 are hypersensitive

to a variety of damaging agents including ionizing radiation and

alkylating agents and exhibit a defect in SSB rejoining [310,312,313].

9.2. XRCC1 cancer-associated variants

For reviews on XRCC1 germline and tumor-associated variants

see [43,314,315]. The XRCC1 Arg399Gln germline variant has a

minor allele frequency of around 10% and has been associated with

cancer risk and responses to various cancer therapies [314]. One

study in Polish women suggests that the presence of the Arg399Gln

variant is associated with increased risk of cervical cancer [316].

The other study suggests that subjects who carry at least one XRCC1

Arg399Gln variant allele have decreased risk for cervical cancer

regardless of papilloma virus infection [317]. These differing results

may be due to a difference in populations characterized or from low

numbers of women studied. A meta-analysis of several studies

demonstrated that the XRCC1 Arg399Gln variant is significantly

associated with prostate cancer in Asian, but not Caucasian men

[318]. However a different meta-analysis of the association of

XRCC1 Arg399Gln variant suggested that it was associated with

significant increase in prostate cancer risk regardless of the popula-

tion studied [319]. Finally postmenopausal women carrying the

Arg399Gln allele appear to be at increased risk for breast cancer

[320].

The XRCC1 Arg194Trp variant was shown to be associated with

a decreased risk of papillary thyroid cancer [321] but with an in-

creased risk for differentiated thyroid cancer [322]. In a meta-anal-

ysis of Arg194Trp, Arg280 and Arg339Gln, no association was

found with gastric cancer [323].

The presence of XRCC1 germline polymorphisms is also associ-

ated with responses to exposures of various types. For example, a

significant difference in the ability to repair ionizing radiation

damage was detected in lymphocytes of individuals who are

homozygous for Arg399Gln, using a modified comet assay [324].

In another study, chromosomal aberrations were measured in

welders exposed to chromium and in a control population. Signif-

icantly increased numbers of aberrations in lymphocytes were de-

tected in individuals homozygous for the Arg399Gln variant [325]

and correlated with levels of chromium in blood. In a third study,

smokers carrying both alleles of the XRCC1 Arg399Gln variant

had significantly increased frequencies of micronuclei and chromo-

somal aberrations [326]. Finally, individuals with non-small cell

lung cancer treated with 45 Gy of ionizing radiation plus platin-

based chemotherapy and carrying the XRCC1 Arg399Gln allele re-

sponded significantly better than those carrying the wild type

Arg399 [327].

10. BER and cancer therapy

For reviews on BER as a cancer therapy target see [328–330].

The intermediates in the BER pathway are usually more toxic than

the initial base lesion. Overexpression of the MPG/AAG DNA glyco-

sylase results in the accumulation of abasic sites that are processed

by APE1, Pol b, and XRCC1/LigIIIa. Overexpression of MPG/AAG

along with down-regulation of Pol b would be expected to lead

to the accumulation of SSBs and DSBs and in fact, sensitizes cells,

including glioma cells, to temozolomide (TMZ). TMZ is currently

being used in the clinic to treat glioblastomas and other tumors

and methylates predominantly the N7 rather than the O6 of guan-

ine [331], thus eliciting BER. Taken together, these results suggest

that a major mechanism of repair of TMZ is BER. In cells that are

down-regulated for Pol b, the dRP group remains attached to the

50 end of the DNA break and is suggested to mediate cell death

via a non-apoptotic pathway [332]. Interestingly, cell death in re-

sponse to the lack of removal of the 50 dRP group has been shown

to result from energy depletion [333]. A combination of inhibition

of BER and NAD+ biosynthesis sensitizes glioma cells to TMZ-

induced cell death [334]. Therefore, modulation of the levels of

BER proteins could be a possible gene therapy approach for killing

cancer cells.

APE1 is also being explored as a cancer therapy target. A

structure-based screening approach using a fluorescence assay to

monitor AP site cleavage identified several APE1 inhibitor com-

pounds [335]. The APE1 Asp148Glu variant appears to be more

sensitive to one of the compounds than wild type APE1. Potentia-

tion of MMS was demonstrated in glioma and melanoma lines with

some of the inhibitor compounds. Using an adapted fluorescence-

based in vitro assay in a high throughput screening format, several

novel APE1 inhibitors were identified. Three compounds emerged

from this screen were found to inactivate AP site cleavage in whole

cell extracts from mammalian cells and enhanced MMS sensitivity

in cells [336]. The compounds exhibit structural diversity, suggest-

ing that they act by different mechanisms. For excellent reviews on

the status of APE1 inhibitors see [337,338].

Pol b is also a potential cancer therapy drug target. Lithocholic

acid (LCA) is a known inhibitor of the binding of Pol b to DNA

and a dRP lyase inhibitor. We have shown that LCA enhances the

cytotoxicity of TMZ significantly in BRCA2 deficient EUFA 423 cells

and also somewhat in the BRCA2+ complemented cells. Thus, BER

and homology-directed repair (HDR) exhibit a synthetic lethal phe-

notype [339], which is not surprising given the important finding

that synthetic lethality is observed in BRCA-deficient cells treated

with PARP inhibitors (for an excellent review on this topic see

[340]). Inhibition of PARP likely leads to in an increase in SSBs

and DSBs during DNA replication that results in cell death. Another

possibility is that PARP inhibitors may cause PARP to be trapped on

DNA, leading to obstruction of the replication fork [340]. Pol bD

cells are very sensitive to PARP inhibitors (for review see [341]).

When PARP1 is deleted in Pol bD MEFS, the cells are no longer

hypersensitive to MMS [342].

McKenna and Goodman have introduced a series of dNTP ana-

logs modified at the a-b or b-c bridging atom. These nonhydrolyz-

able analogs prevent turnover of Pol b and act as a transition state

probe [343]. Based on these data and the emergence of novel strat-

egies for the delivery of dNTP analogs into cells, the authors sug-

gest that these analogs might be part of a new platform for drug

design [344].

DNA ligases are also important cancer drug targets. Tomkinson

and colleagues have developed a ligase inhibitor screen [345,346]

and have employed in silico drug design based upon the structure

of human Ligase I to identify inhibitor compounds. This group

chose compounds that were predicted to bind to the DNA binding

domain from the in silico work to test using a fluorescent ligation

assay and identified several inhibitors of LigI. Two of the com-

pounds that inhibited LigI also inhibited LigIII but not the polymer-

ase gap-filling step. These compounds are competitive inhibitors

and bind to DNA binding domain. They potentiate the killing of



cancer cells with MMS and ionizing radiation, and may be useful in

treating cancer.

11. What have we learned?

To state the obvious we know that BER removes the preponder-

ance of endogenous DNA lesions as well as damages produced dur-

ing episodes of inflammation and exposures to ionizing radiation

and a variety of chemical carcinogens. This conclusion comes from

decades of research where the in vitro biochemical studies showed

that these damages could be removed by the BER enzymes as well

as studies in prokaryotes and numerous mammalian cell types

which demonstrated that in the absence of BER enzymes cells

accumulate mutations and are hypersensitive to a variety of dam-

aging agents. We also know from the knockout mouse models that

as the glycosylase-deficient mice age they accumulate damage and

develop mutations in various organs and when fibroblasts are cul-

tured from embryos of mice that do not survive the embryonic

stage, these MEFs also accumulate mutations and are sensitive to

DNA damaging agents. What is also clear is that the BER process it-

self is required for development since mice deficient for APE1, Pol

b, ligase IIIa, and XRCC1 are embryonic lethals. From the mouse

models, we also learned that the glycosylases that recognize the

damages in DNA have redundant functions since mice deficient

in any single DNA glycosylase have less than profound phenotypes.

This should not have been a surprise since early studies with pro-

karyotes already showed that this was the case when spontaneous

mutagenesis or sensitivity to damaging agents was assessed. More-

over, all of the biochemical assays told us that these enzymes had

redundant substrate specificities. We also know that the damages

repaired by the BER pathway can initiate carcinogenesis since

when more than one glycosylase is knocked out, the mice develop

tumors at an early age. So, taken together, these data strongly sug-

gest that individuals who have compromised BER are at risk for

developing cancer.

This obvious conclusion has led to a large number of studies

asking whether having a particular polymorphic variant in a BER

enzyme can predispose an individual to the risk of cancer. In the

case of OGG1 and APE1, the most common variants, OGG1

Cyr326Sys and APE1 Asp148Glu were examined primarily because

better statistical correlations could be obtained if a larger popula-

tion harbored the polymorphisms. For the most part these data

have been unsatisfactory with often conflicting studies showing

predisposition or not to a particular type of cancer. Again, this

should not be particularly surprising, since both these variants

have wild type or close to wild type enzymatic activity when

examined biochemically. It is more likely that polymorphic vari-

ants that have substantially reduced function would predispose

an individual to the risk of cancer. However, these defective vari-

ants are present at a much lower frequency in the population, thus

statistical power in an epidemiological study is more difficult to at-

tain. What is most probable is that it will take a combination of

polymorphisms to predispose each of us to a particular type of can-

cer, and moreover, this is unlikely to be a unique combination. This

question may be answered sometime in the future when the DNA

from an entire population has been sequenced using massively

parallel sequencing technologies. At this point the bioinformati-

cists should be able to tell us what combinations of mutant alleles

will predispose us to which particular cancer.

Having said this, the MUTYH case is a clear exception. Here, low

frequency variants clearly predispose the individuals who possess

them to colon cancer. Several reasons might account for this. For

example, with highly proliferating cells such as in the colon, the

backup to MUTYH, DNA mismatch repair, may not be enough to

protect the cells from accumulating mutations. An additional

factor is that the target APC gene contains sequences that are par-

ticularly vulnerable to the G? T transversions that MUTYH pro-

tects against. As expected, in the case of MUTYH-associated colon

cancers, the biochemical, function of the particular MUTYH variant

protein usually correlates with the patient’s genotype.

Analysis of mutations in BER genes in tumors should provide in-

sight into tumor development in a particular organ and even more

importantly, the potential role of BER in metastases. Also, as de-

scribed in Section 10 the BER enzymes are important cancer drug

targets since, in their absence, cells are sensitized to a variety of

chemical agents as well as ionizing radiation. Taken together, it

is clear that we need the basic biochemistry and cell biology not

only to guide the epidemiology, but help interpret any epidemio-

logical results. Furthermore, the basic science, including structural

biology, will be central for rational drug design and for developing

strategies to identify small molecule inhibitors for individual

enzymes.

Acknowledgements

This work reported from the Authors’ laboratories was sup-

ported by NCI R01 33657 and P01 CA098993 (to SSW) and P01

CA129186 (JBS, project leader) and R01 CA 080830-(JBS) (to JBS).

The Authors also wish to thank Debra Stern for help with preparing

the manuscript.

References

[1] E.C. Friedberg, G.C. Walker, W. Siede, R.D. Wood, R.A. Schultz, T.Ellenberger, DNA Repair and Mutagenesis, second ed., ASM Press,Washington, DC, 2006.

[2] T. Lindahl, An N-glycosidase from Escherichia coli that releases free uracil fromDNA containing deaminated cytosine residues, Proc. Natl. Acad. Sci. USA 71(1974) 3649–3653.

[3] S. Mitra, T.K. Hazra, R. Roy, S. Ikeda, T. Biswas, J. Lock, I. Boldogh, T. Izumi,Complexities of DNA base excision repair in mammalian cells, Mol. Cells 7(1997) 305–312.

[4] H.E. Krokan, H. Nilsen, F. Skorpen, M. Otterlei, G. Slupphaug, Base excisionrepair of DNA in mammalian cells, FEBS Lett. 476 (2000) 73–77.

[5] S. Mitra, T. Izumi, I. Boldogh, K.K. Bhakat, J.W. Hill, T.K. Hazra, Choreographyof oxidative damage repair in mammalian genomes, Free Radic. Biol. Med. 33(2002) 15–28.

[6] T. Izumi, L.R. Wiederhold, G. Roy, R. Roy, A. Jaiswal, K.K. Bhakat, S. Mitra, T.K.Hazra, Mammalian DNA base excision repair proteins: their interactions androle in repair of oxidative DNA damage, Toxicology 193 (2003) 43–65.

[7] J.C. Fromme, G.L. Verdine, Base excision repair, Adv. Protein Chem. 69 (2004)1–41.

[8] D.E. Barnes, T. Lindahl, Repair and genetic consequences of endogenous DNAbase damage in mammalian cells, Annu. Rev. Genet. 38 (2004) 445–476.

[9] S.S. Wallace, Enzymatic processing of radiation-induced free radical damagein DNA, Radiat. Res. 150 (1998) S60–79.

[10] L. Gros, M.K. Saparbaev, J. Laval, Enzymology of the repair of free radicals-induced DNA damage, Oncogene 21 (2002) 8905–8925.

[11] D.O. Zharkov, Base excision DNA repair, Cell Mol. Life Sci. 65 (2008) 1544–1565.

[12] P.W. Doetsch, R.P. Cunningham, The enzymology of apurinic/apyrimidinicendonucleases, Mutat. Res. 236 (1990) 173–201.

[13] Y. Matsumoto, K. Kim, Excision of deoxyribose phosphate residues by DNApolymerase beta during DNA repair, Science 269 (1995) 699–702.

[14] R. Prasad, W.A. Beard, P.R. Strauss, S.H. Wilson, Human DNA polymerase betadeoxyribose phosphate lyase. Substrate specificity and catalytic mechanism,J. Biol. Chem. 273 (1998) 15263–15270.

[15] V. Bailly, W.G. Verly, Escherichia coli endonuclease III is not an endonucleasebut a beta-elimination catalyst, Biochem. J. 242 (1987) 565–572.

[16] V. Bailly, M. Derydt, W.G. Verly, Delta-elimination in the repair of AP(apurinic/apyrimidinic) sites in DNA, Biochem. J. 261 (1989) 707–713.

[17] D.S. Chen, T. Herman, B. Demple, Two distinct human DNA diesterases thathydrolyze 30-blocking deoxyribose fragments from oxidized DNA, NucleicAcids Res. 19 (1991) 5907–5914.

[18] L. Wiederhold, J.B. Leppard, P. Kedar, F. Karimi-Busheri, A. Rasouli-Nia, M.Weinfeld, A.E. Tomkinson, T. Izumi, R. Prasad, S.H. Wilson, S. Mitra, T.K. Hazra,AP endonuclease-independent DNA base excision repair in human cells, Mol.Cell 15 (2004) 209–220.

[19] R.W. Sobol, J.K. Horton, R. Kuhn, H. Gu, R.K. Singhal, R. Prasad, K. Rajewsky,S.H. Wilson, Requirement of mammalian DNA polymerase-beta in base-excision repair, Nature 379 (1996) 183–186.



[20] R. Prasad, D.D. Shock, W.A. Beard, S.H. Wilson, Substrate channeling inmammalian base excision repair pathways: passing the baton, J. Biol. Chem.285 (2010) 40479–40488.

[21] A.E. Tomkinson, Z.B. Mackey, Structure and function of mammalian DNAligases, Mutat. Res. 407 (1998) 1–9.

[22] K.W. Caldecott, Single-strand break repair and genetic disease, Nat. Rev.Genet. 9 (2008) 619–631.

[23] A. Campalans, S. Marsin, Y. Nakabeppu, R. O’Connor, T.S. Boiteux, J.P.Radicella, XRCC1 interactions with multiple DNA glycosylases: a model forits recruitment to base excision repair, DNA Repair (Amst.) 4 (2005) 826–835.

[24] K.W. Caldecott, S. Aoufouchi, P. Johnson, S. Shall, XRCC1 polypeptide interactswith DNA polymerase beta and possibly poly (ADP-ribose) polymerase, andDNA ligase III is a novel molecular ‘nick-sensor’ in vitro, Nucleic Acids Res. 24(1996) 4387–4394.

[25] K.W. Caldecott, C.K. McKeown, J.D. Tucker, S. Ljungquist, L.H. Thompson, Aninteraction between the mammalian DNA repair protein XRCC1 and DNAligase III, Mol. Cell Biol. 14 (1994) 68–76.

[26] G.L. Dianov, R. Prasad, S.H. Wilson, V.A. Bohr, Role of DNA polymerase beta inthe excision step of long patch mammalian base excision repair, J. Biol. Chem.274 (1999) 13741–13743.

[27] K.H. Almeida, R.W. Sobol, A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification,DNA Repair (Amst.) 6 (2007) 695–711.

[28] J.S. Sung, M.S. DeMott, B. Demple, Long-patch base excision DNA repair of 2-deoxyribonolactone prevents the formation of DNA-protein cross-links withDNA polymerase beta, J. Biol. Chem. 280 (2005) 39095–39103.

[29] M.S. DeMott, E. Beyret, D. Wong, B.C. Bales, J.T. Hwang, M.M. Greenberg, B.Demple, Covalent trapping of human DNA polymerase beta by the oxidativeDNA lesion 2-deoxyribonolactone, J. Biol. Chem. 277 (2002) 7637–7640.

[30] C.F. Huggins, D.R. Chafin, S. Aoyagi, L.A. Henricksen, R.A. Bambara, J.J. Hayes,Flap endonuclease 1 efficiently cleaves base excision repair and DNAreplication intermediates assembled into nucleosomes, Mol. Cell 10 (2002)1201–1211.

[31] L. Balakrishnan, P.D. Brandt, L.A. Lindsey-Boltz, A. Sancar, R.A. Bambara, Longpatch base excision repair proceeds via coordinated stimulation of themultienzyme DNA repair complex, J. Biol. Chem. 284 (2009) 15158–15172.

[32] R. Prasad, G.L. Dianov, V.A. Bohr, S.H. Wilson, FEN1 stimulation of DNApolymerase beta mediates an excision step in mammalian long patch baseexcision repair, J. Biol. Chem. 275 (2000) 4460–4466.

[33] E. Petermann, C. Keil, S.L. Oei, Roles of DNA ligase III and XRCC1 in regulatingthe switch between short patch and long patch BER, DNA Repair (Amst.) 5(2006) 544–555.

[34] M.L. Hegde, T.K. Hazra, S. Mitra, Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells, Cell Res. 18 (2008)27–47.

[35] G. Frosina, Commentary: DNA base excision repair defects in humanpathologies, Free Radic Res. 38 (2004) 1037–1054.

[36] R.J. Hung, J. Hall, P. Brennan, P. Boffetta, Genetic polymorphisms in the baseexcision repair pathway and cancer risk: a HuGE review, Am. J. Epidemiol.162 (2005) 925–942.

[37] T. Nohmi, S.R. Kim, M. Yamada, Modulation of oxidative mutagenesis andcarcinogenesis by polymorphic forms of human DNA repair enzymes, Mutat.Res. 591 (2005) 60–73.

[38] K.K. Chan, Q.M. Zhang, G.L. Dianov, Base excision repair fidelity in normal andcancer cells, Mutagenesis 21 (2006) 173–178.

[39] J.B. Sweasy, T. Lang, D. DiMaio, Is base excision repair a tumor suppressormechanism?, Cell Cycle 5 (2006) 250–259

[40] B. Tudek, Base excision repair modulation as a risk factor for human cancers,Mol. Aspects Med. 28 (2007) 258–275.

[41] M. D’Errico, E. Parlanti, E. Dogliotti, Mechanism of oxidative DNA damagerepair and relevance to human pathology, Mutat. Res. 659 (2008) 4–14.

[42] T. Paz-Elizur, Z. Sevilya, Y. Leitner-Dagan, D. Elinger, L.C. Roisman, Z. Livneh,DNA repair of oxidative DNA damage in human carcinogenesis: potentialapplication for cancer risk assessment and prevention, Cancer Lett. 266(2008) 60–72.

[43] A.A. Nemec, S.S. Wallace, J.B. Sweasy, Variant base excision repair proteins:contributors to genomic instability, Semin. Cancer Biol. 20 (2010) 320–328.

[44] D.M. Wilson 3rd, D. Kim, B.R. Berquist, A.J. Sigurdson, Variation in baseexcision repair capacity, Mutat. Res. 711 (2011) 100–112.

[45] H.E. Krokan, F. Drablos, G. Slupphaug, Uracil in DNA – occurrence,consequences and repair, Oncogene 21 (2002) 8935–8948.

[46] T. Visnes, B. Doseth, H.S. Pettersen, L. Hagen, M.M. Sousa, M. Akbari, M.Otterlei, B. Kavli, G. Slupphaug, H.E. Krokan, Uracil in DNA and its processingby different DNA glycosylases, Philos. Trans. Roy. Soc. Lond., Ser. B: Biol. Sci.364 (2009) 563–568.

[47] M. Otterlei, E. Warbrick, T.A. Nagelhus, T. Haug, G. Slupphaug, M. Akbari, P.A.Aas, K. Steinsbekk, O. Bakke, H.E. Krokan, Post-replicative base excision repairin replication foci, EMBO J. 18 (1999) 3834–3844.

[48] H. Nilsen, I. Rosewell, P. Robins, C.F. Skjelbred, S. Andersen, G. Slupphaug, G.Daly, H.E. Krokan, T. Lindahl, D.E. Barnes, Uracil-DNA glycosylase (UNG)-deficient mice reveal a primary role of the enzyme during DNA replication,Mol. Cell 5 (2000) 1059–1065.

[49] M. Akbari, M. Otterlei, J. Pena-Diaz, P.A. Aas, B. Kavli, N.B. Liabakk, L. Hagen, K.Imai, A. Durandy, G. Slupphaug, H.E. Krokan, Repair of U/G and U/A in DNA byUNG2-associated repair complexes takes place predominantly by short-patch

repair both in proliferating and growth-arrested cells, Nucleic Acids Res. 32(2004) 5486–5498.

[50] B. Kavli, O. Sundheim, M. Akbari, M. Otterlei, H. Nilsen, F. Skorpen, P.A. Aas, L.Hagen, H.E. Krokan, G. Slupphaug, hUNG2 is the major repair enzyme forremoval of uracil from U:A matches, U:G mismatches, and U in single-stranded DNA, with hSMUG1 as a broad specificity backup, J. Biol. Chem. 277(2002) 39926–39936.

[51] B. Kavli, M. Otterlei, G. Slupphaug, H.E. Krokan, Uracil in DNA – generalmutagen, but normal intermediate in acquired immunity, DNA Repair (Amst.)6 (2007) 505–516.

[52] K. Imai, G. Slupphaug, W.I. Lee, P. Revy, S. Nonoyama, N. Catalan, L. Yel, M.Forveille, B. Kavli, H.E. Krokan, H.D. Ochs, A. Fischer, A. Durandy, Humanuracil-DNA glycosylase deficiency associated with profoundly impairedimmunoglobulin class-switch recombination, Nat. Immunol. 4 (2003)1023–1028.

[53] C.D. Mol, A.S. Arvai, G. Slupphaug, B. Kavli, I. Alseth, H.E. Krokan, J.A. Tainer,Crystal structure and mutational analysis of human uracil-DNA glycosylase:structural basis for specificity and catalysis, Cell 80 (1995) 869–878.

[54] R. Savva, K. McAuley-Hecht, T. Brown, L. Pearl, The structural basis of specificbase-excision repair by uracil-DNA glycosylase, Nature 373 (1995) 487–493.

[55] L.H. Pearl, Structure and function in the uracil-DNA glycosylase superfamily,Mutat. Res. 460 (2000) 165–181.

[56] J.E. Wibley, T.R. Waters, K. Haushalter, G.L. Verdine, L.H. Pearl, Structure andspecificity of the vertebrate anti-mutator uracil-DNA glycosylase SMUG1,Mol. Cell 11 (2003) 1647–1659.

[57] B. Hendrich, U. Hardeland, H.H. Ng, J. Jiricny, A. Bird, The thymine glycosylaseMBD4 can bind to the product of deamination at methylated CpG sites,Nature 401 (1999) 301–304.

[58] T.E. Barrett, R. Savva, G. Panayotou, T. Barlow, T. Brown, J. Jiricny, L.H. Pearl,Crystal structure of a G:T/U mismatch-specific DNA glycosylase: mismatchrecognition by complementary-strand interactions, Cell 92 (1998) 117–129.

[59] D. Baba, N. Maita, J.G. Jee, Y. Uchimura, H. Saitoh, K. Sugasawa, F. Hanaoka, H.Tochio, H. Hiroaki, M. Shirakawa, Crystal structure of thymine DNAglycosylase conjugated to SUMO-1, Nature 435 (2005) 979–982.

[60] A. Maiti, M.T. Morgan, E. Pozharski, A.C. Drohat, Crystal structure of humanthymine DNA glycosylase bound to DNA elucidates sequence-specificmismatch recognition, Proc. Natl. Acad. Sci. USA 105 (2008) 8890–8895.

[61] Y.F. He, B.Z. Li, Z. Li, P. Liu, Y. Wang, Q. Tang, J. Ding, Y. Jia, Z. Chen, L. Li, Y. Sun,X. Li, Q. Dai, C.X. Song, K. Zhang, C. He, G.L. Xu, Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA, Science 333(2011) 1303–1307.

[62] S. Ito, L. Shen, Q. Dai, S.C. Wu, L.B. Collins, J.A. Swenberg, C. He, Y. Zhang, Tetproteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine, Science 333 (2011) 1300–1303.

[63] C.D. Mol, A.S. Arvai, T.J. Begley, R.P. Cunningham, J.A. Tainer, Structure andactivity of a thermostable thymine-DNA glycosylase: evidence for basetwisting to remove mismatched normal DNA bases, J. Mol. Biol. 315 (2002)373–384.

[64] R.I. Wakefield, B.O. Smith, X. Nan, A. Free, A. Soteriou, D. Uhrin, A.P. Bird, P.N.Barlow, The solution structure of the domain from MeCP2 that binds tomethylated DNA, J. Mol. Biol. 291 (1999) 1055–1065.

[65] I. Ohki, N. Shimotake, N. Fujita, J. Jee, T. Ikegami, M. Nakao, M. Shirakawa,Solution structure of the methyl-CpG binding domain of human MBD1 incomplex with methylated DNA, Cell 105 (2001) 487–497.

[66] J.K. Zhu, Active DNA demethylation mediated by DNA glycosylases, Annu.Rev. Genet. 43 (2009) 143–166.

[67] E.C. Friedberg, L.B. Meira, Database of mouse strains carrying targetedmutations in genes affecting biological responses to DNA damage Version 7,DNA Repair (Amst.) 5 (2006) 189–209.

[68] E. Larsen, T.J. Meza, L. Kleppa, A. Klungland, Organ and cell specificity of baseexcision repair mutants in mice, Mutat. Res. 614 (2007) 56–68.

[69] H. Nilsen, G. Stamp, S. Andersen, G. Hrivnak, H.E. Krokan, T. Lindahl, D.E.Barnes, Gene-targeted mice lacking the Ung uracil-DNA glycosylase developB-cell lymphomas, Oncogene 22 (2003) 5381–5386.

[70] C.B. Millar, J. Guy, O.J. Sansom, J. Selfridge, E. MacDougall, B. Hendrich, P.D.Keightley, S.M. Bishop, A.R. Clarke, A. Bird, Enhanced CpG mutability andtumorigenesis in MBD4-deficient mice, Science 297 (2002) 403–405.

[71] D. Cortazar, C. Kunz, J. Selfridge, T. Lettieri, Y. Saito, E. MacDougall, A. Wirz, D.Schuermann, A.L. Jacobs, F. Siegrist, R. Steinacher, J. Jiricny, A. Bird, P. Schar,Embryonic lethal phenotype reveals a function of TDG in maintainingepigenetic stability, Nature 470 (2011) 419–423.

[72] P. Broderick, T. Bagratuni, J. Vijayakrishnan, S. Lubbe, I. Chandler, R.S.Houlston, Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1genes in familial colorectal cancer predisposition, BMC Cancer 6 (2006) 243.

[73] Y.W. Moon, W.S. Park, A.O. Vortmeyer, R.J. Weil, Y.S. Lee, T.A. Winters, Z.Zhuang, B.G. Fuller, Mutation of the uracil DNA glycosylase gene detected inglioblastoma, Mutat. Res. 421 (1998) 191–196.

[74] K. Kvaloy, H. Nilsen, K.S. Steinsbekk, A. Nedal, B. Monterotti, M. Akbari, H.E.Krokan, Sequence variation in the human uracil-DNA glycosylase (UNG) gene,Mutat. Res. 461 (2001) 325–338.

[75] C. Schmutte, R. Baffa, L.M. Veronese, Y. Murakumo, R. Fishel, Human thymine-DNA glycosylase maps at chromosome 12q22-q24.1: a region of high loss ofheterozygosity in gastric cancer, Cancer Res. 57 (1997) 3010–3015.

[76] C. Marian, M. Tao, J.B. Mason, D.S. Goerlitz, J. Nie, A. Chanson, J.L.Freudenheim, P.G. Shields, Single nucleotide polymorphisms in uracil-



processing genes, intake of one-carbon nutrients and breast cancer risk, Eur. J.Clin. Nutr. 65 (2011) 683–689.

[77] A. Chanson, L.D. Parnell, E.D. Ciappio, Z. Liu, J.W. Crott, K.L. Tucker, J.B. Mason,Polymorphisms in uracil-processing genes, but not one-carbon nutrients, areassociated with altered DNA uracil concentrations in an urban Puerto Ricanpopulation, Am. J. Clin. Nutr. 89 (2009) 1927–1936.

[78] M. Krzesniak, D. Butkiewicz, A. Samojedny, M. Chorazy, M. Rusin,Polymorphisms in TDG and MGMT genes – epidemiological and functionalstudy in lung cancer patients from Poland, Ann. Hum. Genet. 68 (2004) 300–312.

[79] T. Yamada, T. Koyama, S. Ohwada, K. Tago, I. Sakamoto, S. Yoshimura, K.Hamada, I. Takeyoshi, Y. Morishita, Frameshift mutations in the MBD4/MED1gene in primary gastric cancer with high-frequency microsatellite instability,Cancer Lett. 181 (2002) 115–120.

[80] B. Hao, H. Wang, K. Zhou, Y. Li, X. Chen, G. Zhou, Y. Zhu, X. Miao, W. Tan, Q.Wei, D. Lin, F. He, Identification of genetic variants in base excision repairpathway and their associations with risk of esophageal squamous cellcarcinoma, Cancer Res. 64 (2004) 4378–4384.

[81] R. Miao, H. Gu, H. Liu, Z. Hu, G. Jin, H. Wang, Y. Wang, W. Sun, H. Ma, D. Chen,T. Tian, L. Jin, Q. Wei, D. Lu, W. Huang, H. Shen, Tagging single nucleotidepolymorphisms in MBD4 are associated with risk of lung cancer in a Chinesepopulation, Lung Cancer 62 (2008) 281–286.

[82] J.H. Song, E.J. Maeng, Z. Cao, S.Y. Kim, S.W. Nam, J.Y. Lee, W.S. Park, TheGlu346Lys polymorphism and frameshift mutations of the Methyl-CpGBinding Domain 4 gene in gastrointestinal cancer, Neoplasma 56 (2009)343–347.

[83] E. Chow, L. Lipton, E. Lynch, R. D’Souza, C. Aragona, L. Hodgkin, G. Brown, I.Winship, M. Barker, D. Buchanan, S. Cowie, S. Nasioulas, D. du Sart, J. Young, B.Leggett, J. Jass, F. Macrae, Hyperplastic polyposis syndrome: phenotypicpresentations and the role of MBD4 and MYH, Gastroenterology 131 (2006)30–39.

[84] J. Dong, Z. Hu, Y. Shu, S. Pan, W. Chen, Y. Wang, L. Hu, Y. Jiang, J. Dai, H. Ma, G.Jin, H. Shen, Potentially functional polymorphisms in DNA repair genes andnon-small-cell lung cancer survival: a pathway-based analysis, Mol. Carcinog.(2011).

[85] T. Lindahl, New class of enzymes acting on damaged DNA, Nature 259 (1976)64–66.

[86] T.R. O’Connor, F. Laval, Isolation and structure of a cDNA expressing amammalian 3-methyladenine-DNA glycosylase, EMBO J. 9 (1990) 3337–3342.

[87] D. Chakravarti, G.C. Ibeanu, K. Tano, S. Mitra, Cloning and expression inEscherichia coli of a human cDNA encoding the DNA repair protein N-methylpurine-DNA glycosylase, J. Biol. Chem. 266 (1991) 15710–15715.

[88] T.R. O’Connor, J. Laval, Human cDNA expressing a functional DNA glycosylaseexcising 3-methyladenine and 7-methylguanine, Biochem. Biophys. Res.Commun. 176 (1991) 1170–1177.

[89] L. Samson, B. Derfler, M. Boosalis, K. Call, Cloning and characterization of a 3-methyladenine DNA glycosylase cDNA from human cells whose gene maps tochromosome 16, Proc. Natl. Acad. Sci. USA 88 (1991) 9127–9131.

[90] M.K. Dosanjh, A. Chenna, E. Kim, H. Fraenkel-Conrat, L. Samson, B. Singer, Allfour known cyclic adducts formed in DNA by the vinyl chloride metabolitechloroacetaldehyde are released by a human DNA glycosylase, Proc. Natl.Acad. Sci. USA 91 (1994) 1024–1028.

[91] M. Saparbaev, K. Kleibl, J. Laval, Escherichia coli, Saccharomyces cerevisiae, ratand human 3-methyladenine DNA glycosylases repair 1,N6-ethenoadeninewhen present in DNA, Nucleic Acids Res. 23 (1995) 3750–3755.

[92] M. Saparbaev, J. Laval, Excision of hypoxanthine from DNA containing dIMPresidues by the Escherichia coli, yeast, rat, and human alkylpurine DNAglycosylases, Proc. Natl. Acad. Sci. USA 91 (1994) 5873–5877.

[93] T. Bessho, R. Roy, K. Yamamoto, H. Kasai, S. Nishimura, K. Tano, S. Mitra,Repair of 8-hydroxyguanine in DNA by mammalian N-methylpurine-DNAglycosylase, Proc. Natl. Acad. Sci. USA 90 (1993) 8901–8904.

[94] C.Y. Lee, J.C. Delaney, M. Kartalou, G.M. Lingaraju, A. Maor-Shoshani, J.M.Essigmann, L.D. Samson, Recognition and processing of a new repertoire ofDNA substrates by human 3-methyladenine DNA glycosylase (AAG),Biochemistry 48 (2009) 1850–1861.

[95] A.Y. Lau, O.D. Scharer, L. Samson, G.L. Verdine, T. Ellenberger, Crystalstructure of a human alkylbase-DNA repair enzyme complexed to DNA:mechanisms for nucleotide flipping and base excision, Cell 95 (1998) 249–258.

[96] B.P. Engelward, G. Weeda, M.D. Wyatt, J.L. Broekhof, J. de Wit, I. Donker, J.M.Allan, B. Gold, J.H. Hoeijmakers, L.D. Samson, Base excision repair deficientmice lacking the Aag alkyladenine DNA glycosylase, Proc. Natl. Acad. Sci. USA94 (1997) 13087–13092.

[97] R.H. Elder, J.G. Jansen, R.J. Weeks, M.A. Willington, B. Deans, A.J. Watson, K.J.Mynett, J.A. Bailey, D.P. Cooper, J.A. Rafferty, M.C. Heeran, S.W. Wijnhoven,A.A. van Zeeland, G.P. Margison, Alkylpurine-DNA-N-glycosylase knockoutmice show increased susceptibility to induction of mutations by methylmethanesulfonate, Mol. Cell Biol. 18 (1998) 5828–5837.

[98] S. Wirtz, G. Nagel, L. Eshkind, M.F. Neurath, L.D. Samson, B. Kaina, Both baseexcision repair and O6-methylguanine-DNA methyltransferase protectagainst methylation-induced colon carcinogenesis, Carcinogenesis 31(2010) 2111–2117.

[99] L.B. Meira, J.M. Bugni, S.L. Green, C.W. Lee, B. Pang, D. Borenshtein, B.H.Rickman, A.B. Rogers, C.A. Moroski-Erkul, J.L. McFaline, D.B. Schauer, P.C.Dedon, J.G. Fox, L.D. Samson, DNA damage induced by chronic inflammation

contributes to colon carcinogenesis in mice, J. Clin. Invest. 118 (2008) 2516–2525.

[100] B.P. Engelward, A. Dreslin, J. Christensen, D. Huszar, C. Kurahara, L. Samson,Repair-deficient 3-methyladenine DNA glycosylase homozygous mutantmouse cells have increased sensitivity to alkylation-induced chromosomedamage and cell killing, EMBO J. 15 (1996) 945–952.

[101] R.B. Roth, L.D. Samson, 3-Methyladenine DNA glycosylase-deficient Aag nullmice display unexpected bone marrow alkylation resistance, Cancer Res. 62(2002) 656–660.

[102] T. Coquerelle, J. Dosch, B. Kaina, Overexpression of N-methylpurine-DNAglycosylase in Chinese hamster ovary cells renders them more sensitive tothe production of chromosomal aberrations by methylating agents – a case ofimbalanced DNA repair, Mutat. Res. 336 (1995) 9–17.

[103] S. Zienolddiny, D. Campa, H. Lind, D. Ryberg, V. Skaug, L. Stangeland, D.H.Phillips, F. Canzian, A. Haugen, Polymorphisms of DNA repair genes and riskof non-small cell lung cancer, Carcinogenesis 27 (2006) 560–567.

[104] C.A. Haiman, R.R. Garcia, C. Hsu, L. Xia, H. Ha, X. Sheng, L. Le Marchand, L.N.Kolonel, B.E. Henderson, M.R. Stallcup, G.L. Greene, M.F. Press, Screening andassociation testing of common coding variation in steroid hormone receptorco-activator and co-repressor genes in relation to breast cancer risk: theMultiethnic Cohort, BMC Cancer 9 (2009) 43.

[105] M. Rusin, A. Samojedny, C.C. Harris, M. Chorazy, Novel geneticpolymorphisms in DNA repair genes: O(6)-methylguanine-DNAmethyltransferase (MGMT) and N-methylpurine-DNA glycosylase (MPG) inlung cancer patients from Poland, Hum. Mutat. 14 (1999) 269–270.

[106] L. Mirabello, K. Yu, S.I. Berndt, L. Burdett, Z. Wang, S. Chowdhury, K. Teshome,A. Uzoka, A. Hutchinson, T. Grotmol, C. Douglass, R.B. Hayes, R.N. Hoover, S.A.Savage, A comprehensive candidate gene approach identifies geneticvariation associated with osteosarcoma, BMC Cancer 11 (2011) 209.

[107] R. Lu, H.M. Nash, G.L. Verdine, A mammalian DNA repair enzyme that excisesoxidatively damaged guanines maps to a locus frequently lost in lung cancer,Curr. Biol. 7 (1997) 397–407.

[108] K. Arai, K. Morishita, K. Shinmura, T. Kohno, S.R. Kim, T. Nohmi, M. Taniwaki,S. Ohwada, J. Yokota, Cloning of a human homolog of the yeast OGG1 genethat is involved in the repair of oxidative DNA damage, Oncogene 14 (1997)2857–2861.

[109] H. Aburatani, Y. Hippo, T. Ishida, R. Takashima, C. Matsuba, T. Kodama, M.Takao, A. Yasui, K. Yamamoto, M. Asano, Cloning and characterization ofmammalian 8-hydroxyguanine-specific DNA glycosylase/apurinic,apyrimidinic lyase, a functional mutM homologue, Cancer Res. 57 (1997)2151–2156.

[110] J.P. Radicella, C. Dherin, C. Desmaze, M.S. Fox, S. Boiteux, Cloning andcharacterization of hOGG1, a human homolog of the OGG1 gene ofSaccharomyces cerevisiae, Proc. Natl. Acad. Sci. USA 94 (1997) 8010–8015.

[111] T. Roldan-Arjona, Y.F. Wei, K.C. Carter, A. Klungland, C. Anselmino, R.P. Wang,M. Augustus, T. Lindahl, Molecular cloning and functional expression of ahuman cDNA encoding the antimutator enzyme 8-hydroxyguanine-DNAglycosylase, Proc. Natl. Acad. Sci. USA 94 (1997) 8016–8020.

[112] M. Bjoras, L. Luna, B. Johnsen, E. Hoff, T. Haug, T. Rognes, E. Seeberg, Oppositebase-dependent reactions of a human base excision repair enzyme on DNAcontaining 7,8-dihydro-8-oxoguanine and abasic sites, EMBO J. 16 (1997)6314–6322.

[113] P.M. Girard, C. D’Ham, J. Cadet, S. Boiteux, Opposite base-dependent excisionof 7,8-dihydro-8-oxoadenine by the Ogg1 protein of Saccharomyces cerevisiae,Carcinogenesis 19 (1998) 1299–1305.

[114] D.O. Zharkov, T.A. Rosenquist, S.E. Gerchman, A.P. Grollman, Substratespecificity and reaction mechanism of murine 8-oxoguanine-DNAglycosylase, J. Biol. Chem. 275 (2000) 28607–28617.

[115] K. Asagoshi, T. Yamada, Y. Okada, H. Terato, Y. Ohyama, S. Seki, H. Ide,Recognition of formamidopyrimidine by Escherichia coli and mammalianthymine glycol glycosylases. Distinctive paired base effects and biologicaland mechanistic implications, J. Biol. Chem. 275 (2000) 24781–24786.

[116] K. Asagoshi, T. Yamada, H. Terato, Y. Ohyama, Y. Monden, T. Arai, S.Nishimura, H. Aburatani, T. Lindahl, H. Ide, Distinct repair activities ofhuman 7,8-dihydro-8-oxoguanine DNA glycosylase andformamidopyrimidine DNA glycosylase for formamidopyrimidine and 7,8-dihydro-8-oxoguanine, J. Biol. Chem. 275 (2000) 4956–4964.

[117] S.D. Bruner, D.P. Norman, G.L. Verdine, Structural basis for recognition andrepair of the endogenous mutagen 8-oxoguanine in DNA, Nature 403 (2000)859–866.

[118] M. Bjoras, E. Seeberg, L. Luna, L.H. Pearl, T.E. Barrett, Reciprocal ‘‘flipping’’underlies substrate recognition and catalytic activation by the human 8-oxo-guanine DNA glycosylase, J. Mol. Biol. 317 (2002) 171–177.

[119] L.G. Brieba, B.F. Eichman, R.J. Kokoska, S. Doublie, T.A. Kunkel, T. Ellenberger,Structural basis for the dual coding potential of 8-oxoguanosine by a high-fidelity DNA polymerase, EMBO J. 23 (2004) 3452–3461.

[120] G.W. Hsu, M. Ober, T. Carell, L.S. Beese, Error-prone replication of oxidativelydamaged DNA by a high-fidelity DNA polymerase, Nature 431 (2004)217–221.

[121] K.G. Au, M. Cabrera, J.H. Miller, P. Modrich, Escherichia colimutY gene productis required for specific A-G—-C.G mismatch correction, Proc. Natl. Acad. Sci.USA 85 (1988) 9163–9166.

[122] J.P. McGoldrick, Y.C. Yeh, M. Solomon, J.M. Essigmann, A.L. Lu,Characterization of a mammalian homolog of the Escherichia coli MutYmismatch repair protein, Mol. Cell Biol. 15 (1995) 989–996.



[123] A.L. Lu, J.J. Tsai-Wu, J. Cillo, DNA determinants and substrate specificities ofEscherichia coli MutY, J. Biol. Chem. 270 (1995) 23582–23588.

[124] M.M. Slupska, C. Baikalov, W.M. Luther, J.H. Chiang, Y.F. Wei, J.H. Miller,Cloning and sequencing a human homolog (hMYH) of the Escherichia colimutY gene whose function is required for the repair of oxidative DNAdamage, J. Bacteriol. 178 (1996) 3885–3892.

[125] M.M. Slupska, W.M. Luther, J.H. Chiang, H. Yang, J.H. Miller, Functionalexpression of hMYH, a human homolog of the Escherichia coli MutY protein, J.Bacteriol. 181 (1999) 6210–6213.

[126] C.J. Wiederholt, M.O. Delaney, M.A. Pope, S.S. David, M.M. Greenberg, Repairof DNA containing Fapy.dG and its beta-C-nucleoside analogue byformamidopyrimidine DNA glycosylase and MutY, Biochemistry 42 (2003)9755–9760.

[127] M.A. Pope, S.S. David, DNA damage recognition and repair by the murineMutY homologue, DNA Repair (Amst.) 4 (2005) 91–102.

[128] Y. Guan, R.C. Manuel, A.S. Arvai, S.S. Parikh, C.D. Mol, J.H. Miller, S. Lloyd, J.A.Tainer, MutY catalytic core, mutant and bound adenine structures definespecificity for DNA repair enzyme superfamily, Nat. Struct. Biol. 5 (1998)1058–1064.

[129] J.C. Fromme, A. Banerjee, S.J. Huang, G.L. Verdine, Structural basis for removalof adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase,Nature 427 (2004) 652–656.

[130] M.L. Michaels, L. Pham, Y. Nghiem, C. Cruz, J.H. Miller, MutY, an adenineglycosylase active on G–A mispairs, has homology to endonuclease III,Nucleic Acids Res. 18 (1990) 3841–3845.

[131] R.P. Cunningham, DNA glycosylases, Mutat. Res. 383 (1997) 189–196.[132] A. Mazurek, M. Berardini, R. Fishel, Activation of human MutS homologs by 8-

oxo-guanine DNA damage, J. Biol. Chem. 277 (2002) 8260–8266.[133] C. Colussi, E. Parlanti, P. Degan, G. Aquilina, D. Barnes, P. Macpherson, P.

Karran, M. Crescenzi, E. Dogliotti, M. Bignami, The mammalian mismatchrepair pathway removes DNA 8-oxodGMP incorporated from the oxidizeddNTP pool, Curr. Biol. 12 (2002) 912–918.

[134] P. Macpherson, F. Barone, G. Maga, F. Mazzei, P. Karran, M. Bignami, 8-Oxoguanine incorporation into DNA repeats in vitro and mismatchrecognition by MutSalpha, Nucleic Acids Res. 33 (2005) 5094–5105.

[135] A. Klungland, I. Rosewell, S. Hollenbach, E. Larsen, G. Daly, B. Epe, E. Seeberg,T. Lindahl, D.E. Barnes, Accumulation of premutagenic DNA lesions in micedefective in removal of oxidative base damage, Proc. Natl. Acad. Sci. USA 96(1999) 13300–13305.

[136] O. Minowa, T. Arai, M. Hirano, Y. Monden, S. Nakai, M. Fukuda, M. Itoh, H.Takano, Y. Hippou, H. Aburatani, K. Masumura, T. Nohmi, S. Nishimura, T.Noda, Mmh/Ogg1 gene inactivation results in accumulation of 8-hydroxyguanine in mice, Proc. Natl. Acad. Sci. USA 97 (2000) 4156–4161.

[137] M. Osterod, S. Hollenbach, J.G. Hengstler, D.E. Barnes, T. Lindahl, B. Epe, Age-related and tissue-specific accumulation of oxidative DNA base damage in7,8-dihydro-8-oxoguanine-DNA glycosylase (Ogg1) deficient mice,Carcinogenesis 22 (2001) 1459–1463.

[138] T. Arai, V.P. Kelly, O. Minowa, T. Noda, S. Nishimura, High accumulation ofoxidative DNA damage, 8-hydroxyguanine, in Mmh/Ogg1 deficient mice bychronic oxidative stress, Carcinogenesis 23 (2002) 2005–2010.

[139] M. Kunisada, K. Sakumi, Y. Tominaga, A. Budiyanto, M. Ueda, M. Ichihashi, Y.Nakabeppu, C. Nishigori, 8-Oxoguanine formation induced by chronic UVBexposure makes Ogg1 knockout mice susceptible to skin carcinogenesis,Cancer Res. 65 (2005) 6006–6010.

[140] Y. Xie, H. Yang, C. Cunanan, K. Okamoto, D. Shibata, J. Pan, D.E. Barnes, T.Lindahl, M. McIlhatton, R. Fishel, J.H. Miller, Deficiencies in mouse Myh andOgg1 result in tumor predisposition and G to T mutations in codon 12 of theK-ras oncogene in lung tumors, Cancer Res. 64 (2004) 3096–3102.

[141] S. Hirano, Y. Tominaga, A. Ichinoe, Y. Ushijima, D. Tsuchimoto, Y. Honda-Ohnishi, T. Ohtsubo, K. Sakumi, Y. Nakabeppu, Mutator phenotype ofMUTYH-null mouse embryonic stem cells, J. Biol. Chem. 278 (2003) 38121–38124.

[142] M.T. Russo, G. De Luca, P. Degan, E. Parlanti, E. Dogliotti, D.E. Barnes, T.Lindahl, H. Yang, J.H. Miller, M. Bignami, Accumulation of the oxidative baselesion 8-hydroxyguanine in DNA of tumor-prone mice defective in both theMyh and Ogg1 DNA glycosylases, Cancer Res. 64 (2004) 4411–4414.

[143] J.M. Weiss, E.L. Goode, W.C. Ladiges, C.M. Ulrich, Polymorphic variation inhOGG1 and risk of cancer: a review of the functional and epidemiologicliterature, Mol. Carcinog. 42 (2005) 127–141.

[144] H. Li, X. Hao, W. Zhang, Q. Wei, K. Chen, The hOGG1 Ser326Cys polymorphismand lung cancer risk: a meta-analysis, Cancer Epidemiol. Biomarkers Prev. 17(2008) 1739–1745.

[145] C.H. Chang, C.F. Hsiao, G.C. Chang, Y.H. Tsai, Y.M. Chen, M.S. Huang, W.C. Su,W.S. Hsieh, P.C. Yang, C.J. Chen, C.A. Hsiung, Interactive effect of cigarettesmoking with human 8-oxoguanine DNA N-glycosylase 1 (hOGG1)polymorphisms on the risk of lung cancer: a case-control study in Taiwan,Am. J. Epidemiol. 170 (2009) 695–702.

[146] E. Pawlowska, K. Janik-Papis, M. Rydzanicz, K. Zuk, D. Kaczmarczyk, J.Olszewski, K. Szyfter, J. Blasiak, A. Morawiec-Sztandera, The Cys326 allele ofthe 8-oxoguanine DNA N-glycosylase 1 gene as a risk factor in smoking- anddrinking-associated larynx cancer, Tohoku J. Exp. Med. 219 (2009) 269–275.

[147] D. Gu, M. Wang, Z. Zhang, J. Chen, Lack of association between the hOGG1Ser326Cys polymorphism and breast cancer risk: evidence from 11 case-control studies, Breast Cancer Res. Treat. 122 (2010) 527–531.

[148] K. Curtin, W.S. Samowitz, R.K. Wolff, C.M. Ulrich, B.J. Caan, J.D. Potter, M.L.Slattery, Assessing tumor mutations to gain insight into base excision repair

sequence polymorphisms and smoking in colon cancer, Cancer Epidemiol.Biomarkers Prev. 18 (2009) 3384–3388.

[149] C.J. Liu, T.C. Hsia, R.Y. Tsai, S.S. Sun, C.H. Wang, C.C. Lin, C.W. Tsai, C.Y. Huang,C.M. Hsu, D.T. Bau, The joint effect of hOGG1 single nucleotide polymorphismand smoking habit on lung cancer in Taiwan, Anticancer Res. 30 (2010) 4141–4145.

[150] M. Stanczyk, T. Sliwinski, M. Cuchra, M. Zubowska, A. Bielecka-Kowalska, M.Kowalski, J. Szemraj, W. Mlynarski, I. Majsterek, The association ofpolymorphisms in DNA base excision repair genes XRCC1, OGG1 andMUTYH with the risk of childhood acute lymphoblastic leukemia, Mol. Biol.Rep. 38 (2011) 445–451.

[151] H. Zhao, C. Qin, F. Yan, B. Wu, Q. Cao, M. Wang, Z. Zhang, C. Yin, hOGG1Ser326Cys polymorphism and renal cell carcinoma risk in a Chinesepopulation, DNA Cell Biol. 30 (2011) 317–321.

[152] X. Chen, J. Wang, W. Guo, X. Liu, C. Sun, Z. Cai, Y. Fan, Y. Wang, Two functionalvariations in 50-UTR of hoGG1 gene associated with the risk of breast cancerin Chinese, Breast Cancer Res. Treat. 127 (2011) 795–803.

[153] M. Audebert, J.P. Radicella, M. Dizdaroglu, Effect of single mutations in theOGG1 gene found in human tumors on the substrate specificity of the Ogg1protein, Nucleic Acids Res. 28 (2000) 2672–2678.

[154] C. Dherin, J.P. Radicella, M. Dizdaroglu, S. Boiteux, Excision of oxidativelydamaged DNA bases by the human alpha-hOgg1 protein and thepolymorphic alpha-hOgg1(Ser326Cys) protein which is frequently found inhuman populations, Nucleic Acids Res. 27 (1999) 4001–4007.

[155] V.S. Sidorenko, A.P. Grollman, P. Jaruga, M. Dizdaroglu, D.O. Zharkov,Substrate specificity and excision kinetics of natural polymorphic variantsand phosphomimetic mutants of human 8-oxoguanine-DNA glycosylase,FEBS J. 276 (2009) 5149–5162.

[156] K. Janssen, K. Schlink, W. Gotte, B. Hippler, B. Kaina, F. Oesch, DNA repairactivity of 8-oxoguanine DNA glycosylase 1 (OGG1) in human lymphocytes isnot dependent on genetic polymorphism Ser326/Cys326, Mutat. Res. 486(2001) 207–216.

[157] T. Kohno, K. Shinmura, M. Tosaka, M. Tani, S.R. Kim, H. Sugimura, T. Nohmi, H.Kasai, J. Yokota, Genetic polymorphisms and alternative splicing of thehOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damagedDNA, Oncogene 16 (1998) 3219–3225.

[158] A. Yamane, T. Kohno, K. Ito, N. Sunaga, K. Aoki, K. Yoshimura, H. Murakami, Y.Nojima, J. Yokota, Differential ability of polymorphic OGG1 proteins tosuppress mutagenesis induced by 8-hydroxyguanine in human cell in vivo,Carcinogenesis 25 (2004) 1689–1694.

[159] J.W. Hill, M.K. Evans, Dimerization and opposite base-dependent catalyticimpairment of polymorphic S326C OGG1 glycosylase, Nucleic Acids Res. 34(2006) 1620–1632.

[160] D.J. Smart, J.K. Chipman, N.J. Hodges, Activity of OGG1 variants in the repair ofpro-oxidant-induced 8-oxo-20-deoxyguanosine, DNA Repair (Amst.) 5 (2006)1337–1345.

[161] A. Bravard, M. Vacher, E. Moritz, L. Vaslin, J. Hall, B. Epe, J.P. Radicella,Oxidation status of human OGG1-S326C polymorphic variant determinescellular DNA repair capacity, Cancer Res. 69 (2009) 3642–3649.

[162] L. Luna, V. Rolseth, G.A. Hildrestrand, M. Otterlei, F. Dantzer, M. Bjoras, E.Seeberg, Dynamic relocalization of hOGG1 during the cell cycle is disruptedin cells harbouring the hOGG1-Cys326 polymorphic variant, Nucleic AcidsRes. 33 (2005) 1813–1824.

[163] A.R. Dallosso, S. Dolwani, N. Jones, S. Jones, J. Colley, J. Maynard, S.Idziaszczyk, V. Humphreys, J. Arnold, A. Donaldson, D. Eccles, A. Ellis, D.G.Evans, I.M. Frayling, F.J. Hes, R.S. Houlston, E.R. Maher, M. Nielsen, S. Parry, E.Tyler, V. Moskvina, J.P. Cheadle, J.R. Sampson, Inherited predisposition tocolorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1,NUDT1, NTH1 or NEIL 1, 2 or 3, Gut 57 (2008) 1252–1255.

[164] M. Forsbring, E.S. Vik, B. Dalhus, T.H. Karlsen, A. Bergquist, E. Schrumpf, M.Bjoras, K.M. Boberg, I. Alseth, Catalytically impaired hMYH and NEIL1 mutantproteins identified in patients with primary sclerosing cholangitis andcholangiocarcinoma, Carcinogenesis 30 (2009) 1147–1154.

[165] S. Chevillard, J.P. Radicella, C. Levalois, J. Lebeau, M.F. Poupon, S. Oudard, B.Dutrillaux, S. Boiteux, Mutations in OGG1, a gene involved in the repair ofoxidative DNA damage, are found in human lung and kidney tumours,Oncogene 16 (1998) 3083–3086.

[166] M. Audebert, S. Chevillard, C. Levalois, G. Gyapay, A. Vieillefond, J. Klijanienko,P. Vielh, A.K. El Naggar, S. Oudard, S. Boiteux, J.P. Radicella, Alterations of theDNA repair gene OGG1 in human clear cell carcinomas of the kidney, CancerRes. 60 (2000) 4740–4744.

[167] N. Al-Tassan, N.H. Chmiel, J. Maynard, N. Fleming, A.L. Livingston, G.T.Williams, A.K. Hodges, D.R. Davies, S.S. David, J.R. Sampson, J.P. Cheadle,Inherited variants of MYH associated with somatic G:C–>T:A mutations incolorectal tumors, Nat. Genet. 30 (2002) 227–232.

[168] J.P. Cheadle, J.R. Sampson, MUTYH-associated polyposis – from defect in baseexcision repair to clinical genetic testing, DNA Repair (Amst.) 6 (2007) 274–279.

[169] S.S. David, V.L. O’Shea, S. Kundu, Base-excision repair of oxidative DNAdamage, Nature 447 (2007) 941–950.

[170] K.W. Jasperson, T.M. Tuohy, D.W. Neklason, R.W. Burt, Hereditary andfamilial colon cancer, Gastroenterology 138 (2010) 2044–2058.

[171] J.P. Cheadle, J.R. Sampson, Exposing the MYtH about base excision repair andhuman inherited disease, Hum. Mol. Genet. 12 Spec. No. 2 (2003) R159–R165.

[172] S. Jones, P. Emmerson, J. Maynard, J.M. Best, S. Jordan, G.T. Williams, J.R.Sampson, J.P. Cheadle, Biallelic germline mutations in MYH predispose to



multiple colorectal adenoma and somatic G:C–>T:A mutations, Hum. Mol.Genet. 11 (2002) 2961–2967.

[173] K.S. Boparai, E. Dekker, S. Van Eeden, M.M. Polak, J.F. Bartelsman, E.M.Mathus-Vliegen, J.J. Keller, C.J. van Noesel, Hyperplastic polyps and sessileserrated adenomas as a phenotypic expression of MYH-associated polyposis,Gastroenterology 135 (2008) 2014–2018.

[174] S. Vogt, N. Jones, D. Christian, C. Engel, M. Nielsen, A. Kaufmann, V. Steinke,H.F. Vasen, P. Propping, J.R. Sampson, F.J. Hes, S. Aretz, Expanded extracolonictumor spectrum in MUTYH-associated polyposis, Gastroenterology 137(2009) 1976–1985. e1971–e1910.

[175] A. Banerjee, W.L. Santos, G.L. Verdine, Structure of a DNA glycosylasesearching for lesions, Science 311 (2006) 1153–1157.

[176] A.R. Dunn, N.M. Kad, S.R. Nelson, D.M. Warshaw, S.S. Wallace, Single Qdot-labeled glycosylase molecules use a wedge amino acid to probe for lesionswhile scanning along DNA, Nucleic Acids Res. 39 (2011) 7487–7498.

[177] N.H. Chmiel, A.L. Livingston, S.S. David, Insight into the functionalconsequences of inherited variants of the hMYH adenine glycosylaseassociated with colorectal cancer: complementation assays with hMYHvariants and pre-steady-state kinetics of the corresponding mutated E. colienzymes, J. Mol. Biol. 327 (2003) 431–443.

[178] P. Alhopuro, A.R. Parker, R. Lehtonen, S. Enholm, H.J. Jarvinen, J.P. Mecklin, A.Karhu, J.R. Eshleman, L.A. Aaltonen, A novel functionally deficient MYHvariant in individuals with colorectal adenomatous polyposis, Hum. Mutat.26 (2005) 393.

[179] H. Bai, S. Jones, X. Guan, T.M. Wilson, J.R. Sampson, J.P. Cheadle, A.L. Lu,Functional characterization of two human MutY homolog (hMYH) missensemutations (R227W and V232F) that lie within the putative hMSH6 bindingdomain and are associated with hMYH polyposis, Nucleic Acids Res. 33(2005) 597–604.

[180] H. Bai, S. Grist, J. Gardner, G. Suthers, T.M. Wilson, A.L. Lu, Functionalcharacterization of human MutY homolog (hMYH) missense mutation(R231L) that is linked with hMYH-associated polyposis, Cancer Lett. 250(2007) 74–81.

[181] M. Ali, H. Kim, S. Cleary, C. Cupples, S. Gallinger, R. Bristow, Characterizationof mutant MUTYH proteins associated with familial colorectal cancer,Gastroenterology 135 (2008) 499–507.

[182] S. Kundu, M.K. Brinkmeyer, A.L. Livingston, S.S. David, Adenine removalactivity and bacterial complementation with the human MutY homologue(MUTYH) and Y165C, G382D, P391L and Q324R variants associated withcolorectal cancer, DNA Repair (Amst.) 8 (2009) 1400–1410.

[183] V.G. D’Agostino, A. Minoprio, P. Torreri, I. Marinoni, C. Bossa, T.C. Petrucci,A.M. Albertini, G.N. Ranzani, M. Bignami, F. Mazzei, Functional analysis ofMUTYH mutated proteins associated with familial adenomatous polyposis,DNA Repair (Amst.) 9 (2010) 700–707.

[184] M. Goto, K. Shinmura, Y. Nakabeppu, H. Tao, H. Yamada, T. Tsuneyoshi, H.Sugimura, Adenine DNA glycosylase activity of 14 human MutY homolog(MUTYH) variant proteins found in patients with colorectal polyposis andcancer, Hum. Mutat. 31 (2010) E1861–1874.

[185] S. Molatore, M.T. Russo, V.G. D’Agostino, F. Barone, Y. Matsumoto, A.M.Albertini, A. Minoprio, P. Degan, F. Mazzei, M. Bignami, G.N. Ranzani, MUTYHmutations associated with familial adenomatous polyposis: functionalcharacterization by a mammalian cell-based assay, Hum. Mutat. 31 (2010)159–166.

[186] H. Maki, M. Sekiguchi, MutT protein specifically hydrolyses a potentmutagenic substrate for DNA synthesis, Nature 355 (1992) 273–275.

[187] K. Sakumi, M. Furuichi, T. Tsuzuki, T. Kakuma, S. Kawabata, H. Maki, M.Sekiguchi, Cloning and expression of cDNA for a human enzyme thathydrolyzes 8-oxo-dGTP, a mutagenic substrate for DNA synthesis, J. Biol.Chem. 268 (1993) 23524–23530.

[188] M. Furuichi, M.C. Yoshida, H. Oda, T. Tajiri, Y. Nakabeppu, T. Tsuzuki, M.Sekiguchi, Genomic structure and chromosome location of the human mutThomologue gene MTH1 encoding 8-oxo-dGTPase for prevention of A:T to C:Gtransversion, Genomics 24 (1994) 485–490.

[189] D.M. Noll, A. Gogos, J.A. Granek, N.D. Clarke, The C-terminal domain of theadenine-DNA glycosylase MutY confers specificity for 8-oxoguanine.adeninemispairs and may have evolved from MutT, an 8-oxo-dGTPase, Biochemistry38 (1999) 6374–6379.

[190] N.H. Chmiel, M.P. Golinelli, A.W. Francis, S.S. David, Efficientrecognition of substrates and substrate analogs by the adenineglycosylase MutY requires the C-terminal domain, Nucleic Acids Res.29 (2001) 553–564.

[191] M. Nielsen, M.C. Joerink-van de Beld, N. Jones, S. Vogt, C.M. Tops, H.F. Vasen,J.R. Sampson, S. Aretz, F.J. Hes, Analysis of MUTYH genotypes and colorectalphenotypes in patients With MUTYH-associated polyposis, Gastroenterology136 (2009) 471–476.

[192] M.E. Croitoru, S.P. Cleary, N. Di Nicola, M. Manno, T. Selander, M. Aronson, M.Redston, M. Cotterchio, J. Knight, R. Gryfe, S. Gallinger, Association betweenbiallelic and monoallelic germline MYH gene mutations and colorectal cancerrisk, J. Natl. Cancer Inst. 96 (2004) 1631–1634.

[193] M.A. Jenkins, M.E. Croitoru, N. Monga, S.P. Cleary, M. Cotterchio, J.L. Hopper, S.Gallinger, Risk of colorectal cancer in monoallelic and biallelic carriers ofMYH mutations: a population-based case-family study, Cancer Epidemiol.Biomarkers Prev. 15 (2006) 312–314.

[194] S.P. Cleary, M. Cotterchio, M.A. Jenkins, H. Kim, R. Bristow, R. Green, R. Haile,J.L. Hopper, L. LeMarchand, N. Lindor, P. Parfrey, J. Potter, B. Younghusband, S.Gallinger, Germline MutY human homologue mutations and colorectal

cancer: a multisite case-control study, Gastroenterology 136 (2009) 1251–1260.

[195] N. Jones, S. Vogt, M. Nielsen, D. Christian, P.A. Wark, D. Eccles, E. Edwards,D.G. Evans, E.R. Maher, H.F. Vasen, F.J. Hes, S. Aretz, J.R. Sampson, Increasedcolorectal cancer incidence in obligate carriers of heterozygous mutations inMUTYH, Gastroenterology 137 (2009) 489–494. 494 e481; quiz 725-486.

[196] R. Aspinwall, D.G. Rothwell, T. Roldan-Arjona, C. Anselmino, C.J. Ward, J.P.Cheadle, J.R. Sampson, T. Lindahl, P.C. Harris, I.D. Hickson, Cloning andcharacterization of a functional human homolog of Escherichia coliendonuclease III, Proc. Natl. Acad. Sci. USA 94 (1997) 109–114.

[197] T.P. Hilbert, W. Chaung, R.J. Boorstein, R.P. Cunningham, G.W. Teebor, Cloningand expression of the cDNA encoding the human homologue of the DNArepair enzyme, Escherichia coli endonuclease III, J. Biol. Chem. 272 (1997)6733–6740.

[198] S. Ikeda, T. Biswas, R. Roy, T. Izumi, I. Boldogh, A. Kurosky, A.H. Sarker, S. Seki,S. Mitra, Purification and characterization of human NTH1, a homolog ofEscherichia coli endonuclease III. Direct identification of Lys-212 as the activenucleophilic residue, J. Biol. Chem. 273 (1998) 21585–21593.

[199] L. Eide, L. Luna, E.C. Gustad, P.T. Henderson, J.M. Essigmann, B. Demple, E.Seeberg, Human endonuclease III acts preferentially on DNA damageopposite guanine residues in DNA, Biochemistry 40 (2001) 6653–6659.

[200] T.K. Hazra, A. Das, S. Das, S. Choudhury, Y.W. Kow, R. Roy, Oxidative DNAdamage repair in mammalian cells: a new perspective, DNA Repair (Amst.) 6(2007) 470–480.

[201] M.M. Thayer, H. Ahern, D. Xing, R.P. Cunningham, J.A. Tainer, Novel DNAbinding motifs in the DNA repair enzyme endonuclease III crystal structure,EMBO J. 14 (1995) 4108–4120.

[202] T.K. Hazra, T. Izumi, I. Boldogh, B. Imhoff, Y.W. Kow, P. Jaruga, M. Dizdaroglu,S. Mitra, Identification and characterization of a human DNA glycosylase forrepair of modified bases in oxidatively damaged DNA, Proc. Natl. Acad. Sci.USA 99 (2002) 3523–3528.

[203] H. Dou, C.A. Theriot, A. Das, M.L. Hegde, Y. Matsumoto, I. Boldogh, T.K. Hazra,K.K. Bhakat, S. Mitra, Interaction of the human DNA glycosylase NEIL1 withproliferating cell nuclear antigen. The potential for replication-associatedrepair of oxidized bases in mammalian genomes, J. Biol. Chem. 283 (2008)3130–3140.

[204] M.L. Hegde, C.A. Theriot, A. Das, P.M. Hegde, Z. Guo, R.K. Gary, T.K. Hazra, B.Shen, S. Mitra, Physical and functional interaction between human oxidizedbase-specific DNA glycosylase NEIL1 and flap endonuclease 1, J. Biol. Chem.283 (2008) 27028–27037.

[205] C.A. Theriot, M.L. Hegde, T.K. Hazra, S. Mitra, RPA physically interacts with thehuman DNA glycosylase NEIL1 to regulate excision of oxidative DNA basedamage in primer-template structures, DNA Repair (Amst.) 9 (2010) 643–652.

[206] V. Bandaru, S. Sunkara, S.S. Wallace, J.P. Bond, A novel human DNAglycosylase that removes oxidative DNA damage and is homologous toEscherichia coli endonuclease VIII, DNA Repair (Amst.) 1 (2002) 517–529.

[207] T.K. Hazra, Y.W. Kow, Z. Hatahet, B. Imhoff, I. Boldogh, S.K. Mokkapati, S.Mitra, T. Izumi, Identification and characterization of a novel human DNAglycosylase for repair of cytosine-derived lesions, J. Biol. Chem. 277 (2002)30417–30420.

[208] I. Morland, V. Rolseth, L. Luna, T. Rognes, M. Bjoras, E. Seeberg, Human DNAglycosylases of the bacterial Fpg/MutM superfamily: an alternative pathwayfor the repair of 8-oxoguanine and other oxidation products in DNA, NucleicAcids Res. 30 (2002) 4926–4936.

[209] M. Takao, S. Kanno, K. Kobayashi, Q.M. Zhang, S. Yonei, G.T. van der Horst, A.Yasui, A back-up glycosylase in Nth1 knock-out mice is a functional Nei(endonuclease VIII) homologue, J. Biol. Chem. 277 (2002) 42205–42213.

[210] P. Jaruga, M. Birincioglu, T.A. Rosenquist, M. Dizdaroglu, Mouse NEIL1 proteinis specific for excision of 2,6-diamino-4-hydroxy-5-formamidopyrimidineand 4,6-diamino-5-formamidopyrimidine from oxidatively damaged DNA,Biochemistry 43 (2004) 15909–15914.

[211] A. Katafuchi, T. Nakano, A. Masaoka, H. Terato, S. Iwai, F. Hanaoka, H. Ide,Differential specificity of human and Escherichia coli endonuclease III and VIIIhomologues for oxidative base lesions, J. Biol. Chem. 279 (2004) 14464–14471.

[212] M.M. McTigue, R.A. Rieger, T.A. Rosenquist, C.R. Iden, C.R. De Los Santos,Stereoselective excision of thymine glycol lesions by mammalian cellextracts, DNA Repair (Amst.) 3 (2004) 313–322.

[213] H. Miller, A.S. Fernandes, E. Zaika, M.M. McTigue, M.C. Torres, M. Wente, C.R.Iden, A.P. Grollman, Stereoselective excision of thymine glycol fromoxidatively damaged DNA, Nucleic Acids Res. 32 (2004) 338–345.

[214] Q.M. Zhang, S. Yonekura, M. Takao, A. Yasui, H. Sugiyama, S. Yonei, DNAglycosylase activities for thymine residues oxidized in the methyl group arefunctions of the hNEIL1 and hNTH1 enzymes in human cells, DNA Repair(Amst.) 4 (2005) 71–79.

[215] M.T. Ocampo-Hafalla, A. Altamirano, A.K. Basu, M.K. Chan, J.E. Ocampo, A.Cummings Jr., R.J. Boorstein, R.P. Cunningham, G.W. Teebor, Repair ofthymine glycol by hNth1 and hNeil1 is modulated by base pairing and cis-trans epimerization, DNA Repair (Amst.) 5 (2006) 444–454.

[216] I.R. Grin, G.L. Dianov, D.O. Zharkov, The role of mammalian NEIL1 protein inthe repair of 8-oxo-7,8-dihydroadenine in DNA, FEBS Lett. 584 (2010) 1553–1557.

[217] N. Krishnamurthy, X. Zhao, C.J. Burrows, S.S. David, Superior removal ofhydantoin lesions relative to other oxidized bases by the human DNAglycosylase hNEIL1, Biochemistry 47 (2008) 7137–7146.



[218] X. Zhao, N. Krishnamurthy, C.J. Burrows, S.S. David, Mutation versus repair:NEIL1 removal of hydantoin lesions in single-stranded, bulge, bubble, andduplex DNA contexts, Biochemistry 49 (2010) 1658–1666.

[219] S. Doublie, V. Bandaru, J.P. Bond, S.S. Wallace, The crystal structure of humanendonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required forglycosylase activity, Proc. Natl. Acad. Sci. USA 101 (2004) 10284–10289.

[220] H. Dou, S. Mitra, T.K. Hazra, Repair of oxidized bases in DNA bubble structuresby human DNA glycosylases NEIL1 and NEIL2, J. Biol. Chem. 278 (2003)49679–49684.

[221] M.K. Hailer, P.G. Slade, B.D. Martin, T.A. Rosenquist, K.D. Sugden, Recognitionof the oxidized lesions spiroiminodihydantoin and guanidinohydantoin inDNA by the mammalian base excision repair glycosylases NEIL1 and NEIL2,DNA Repair (Amst.) 4 (2005) 41–50.

[222] D. Banerjee, S.M. Mandal, A. Das, M.L. Hegde, S. Das, K.K. Bhakat, I. Boldogh,P.S. Sarkar, S. Mitra, T.K. Hazra, Preferential repair of oxidized base damage inthe transcribed genes of mammalian cells, J. Biol. Chem. 286 (2011) 6006–6016.

[223] M. Liu, V. Bandaru, J.P. Bond, P. Jaruga, X. Zhao, P.P. Christov, C.J. Burrows, C.J.Rizzo, M. Dizdaroglu, S.S. Wallace, The mouse ortholog of NEIL3 is afunctional DNA glycosylase in vitro and in vivo, Proc. Natl. Acad. Sci. USA107 (2010) 4925–4930.

[224] K. Torisu, D. Tsuchimoto, Y. Ohnishi, Y. Nakabeppu, Hematopoietic tissue-specific expression of mouse Neil3 for endonuclease VIII-like protein, J.Biochem. 138 (2005) 763–772.

[225] M. Takao, Y. Oohata, K. Kitadokoro, K. Kobayashi, S. Iwai, A. Yasui, S. Yonei,Q.M. Zhang, Human Nei-like protein NEIL3 has AP lyase activity specific forsingle-stranded DNA and confers oxidative stress resistance in Escherichia coli

mutant, Genes. Cells 14 (2009) 261–270.[226] M.T. Ocampo, W. Chaung, D.R. Marenstein, M.K. Chan, A. Altamirano, A.K.

Basu, R.J. Boorstein, R.P. Cunningham, G.W. Teebor, Targeted deletion ofmNth1 reveals a novel DNA repair enzyme activity, Mol. Cell Biol. 22 (2002)6111–6121.

[227] M. Takao, S. Kanno, T. Shiromoto, R. Hasegawa, H. Ide, S. Ikeda, A.H. Sarker, S.Seki, J.Z. Xing, X.C. Le, M. Weinfeld, K. Kobayashi, J. Miyazaki, M. Muijtjens,J.H. Hoeijmakers, G. van der Horst, A. Yasui, Novel nuclear and mitochondrialglycosylases revealed by disruption of the mouse Nth1 gene encoding anendonuclease III homolog for repair of thymine glycols, EMBO J. 21 (2002)3486–3493.

[228] V. Vartanian, B. Lowell, I.G. Minko, T.G. Wood, J.D. Ceci, S. George, S.W.Ballinger, C.L. Corless, A.K. McCullough, R.S. Lloyd, The metabolic syndromeresulting from a knockout of the NEIL1 DNA glycosylase, Proc. Natl. Acad. Sci.USA 103 (2006) 1864–1869.

[229] J. Hu, N.C. de Souza-Pinto, K. Haraguchi, B.A. Hogue, P. Jaruga, M.M.Greenberg, M. Dizdaroglu, V.A. Bohr, Repair of formamidopyrimidines inDNA involves different glycosylases: role of the OGG1, NTH1, and NEIL1enzymes, J. Biol. Chem. 280 (2005) 40544–40551.

[230] H. Sampath, A.K. Batra, V. Vartanian, J.R. Carmical, D. Prusak, I.B. King, B.Lowell, L.F. Earley, T.G. Wood, D.L. Marks, A.K. McCullough, R. Stephen,Variable penetrance of metabolic phenotypes and development of high-fatdiet-induced adiposity in NEIL1-deficient mice, Am. J. Physiol. Endocrinol.Metab. 300 (2011) E724–734.

[231] M.K. Chan, M.T. Ocampo-Hafalla, V. Vartanian, P. Jaruga, G. Kirkali, K.L.Koenig, S. Brown, R.S. Lloyd, M. Dizdaroglu, G.W. Teebor, Targeted deletion ofthe genes encoding NTH1 and NEIL1 DNA N-glycosylases reveals theexistence of novel carcinogenic oxidative damage to DNA, DNA Repair(Amst.) 8 (2009) 786–794.

[232] L.M. Roy, P. Jaruga, T.G. Wood, A.K. McCullough, M. Dizdaroglu, R.S. Lloyd,Human polymorphic variants of the NEIL1 DNA glycosylase, J. Biol. Chem. 282(2007) 15790–15798.

[233] K. Shinmura, H. Tao, M. Goto, H. Igarashi, T. Taniguchi, M. Maekawa, T.Takezaki, H. Sugimura, Inactivating mutations of the human baseexcision repair gene NEIL1 in gastric cancer, Carcinogenesis 25 (2004)2311–2317.

[234] M. Goto, K. Shinmura, H. Tao, S. Tsugane, H. Sugimura, Three novel NEIL1promoter polymorphisms in gastric cancer patients, World J. Gastrointest.Oncol. 2 (2010) 117–120.

[235] B. Demple, J.S. Sung, Molecular and biological roles of Ape1 protein inmammalian base excision repair, DNA Repair (Amst.) 4 (2005) 1442–1449.

[236] S. Xanthoudakis, G. Miao, F. Wang, Y.C. Pan, T. Curran, Redox activation ofFos-Jun DNA binding activity is mediated by a DNA repair enzyme, EMBO J.11 (1992) 3323–3335.

[237] A.R. Evans, M. Limp-Foster, M.R. Kelley, Going APE over ref-1, Mutat. Res. 461(2000) 83–108.

[238] B. Demple, T. Herman, D.S. Chen, Cloning and expression of APE, the cDNAencoding the major human apurinic endonuclease: definition of a family ofDNA repair enzymes, Proc. Natl. Acad. Sci. USA 88 (1991) 11450–11454.

[239] C.N. Robson, I.D. Hickson, Isolation of cDNA clones encoding a humanapurinic/apyrimidinic endonuclease that corrects DNA repair andmutagenesis defects in E. coli xth (exonuclease III) mutants, Nucleic AcidsRes. 19 (1991) 5519–5523.

[240] S. Seki, M. Hatsushika, S. Watanabe, K. Akiyama, K. Nagao, K. Tsutsui, cDNAcloning, sequencing, expression and possible domain structure of humanAPEX nuclease homologous to Escherichia coli exonuclease III, Biochim.Biophys. Acta 1131 (1992) 287–299.

[241] M.A. Gorman, S. Morera, D.G. Rothwell, E. de La Fortelle, C.D. Mol, J.A. Tainer,I.D. Hickson, P.S. Freemont, The crystal structure of the human DNA repair

endonuclease HAP1 suggests the recognition of extra-helical deoxyribose atDNA abasic sites, EMBO J. 16 (1997) 6548–6558.

[242] M.Z. Hadi, D.M. Wilson 3rd, Second human protein with homology to theEscherichia coli abasic endonuclease exonuclease III, Environ. Mol. Mutagen36 (2000) 312–324.

[243] P. Burkovics, V. Szukacsov, I. Unk, L. Haracska, Human Ape2 protein has a 30–50 exonuclease activity that acts preferentially on mismatched base pairs,Nucleic Acids Res. 34 (2006) 2508–2515.

[244] P. Burkovics, I. Hajdu, V. Szukacsov, I. Unk, L. Haracska, Role of PCNA-dependent stimulation of 30-phosphodiesterase and 30–50 exonucleaseactivities of human Ape2 in repair of oxidative DNA damage, Nucleic AcidsRes. 37 (2009) 4247–4255.

[245] M.Z. Hadi, K. Ginalski, L.H. Nguyen, D.M. Wilson 3rd, Determinants innuclease specificity of Ape1 and Ape2, human homologues of Escherichia coliexonuclease III, J. Mol. Biol. 316 (2002) 853–866.

[246] J.E. Guikema, R.M. Gerstein, E.K. Linehan, E.K. Cloherty, E. Evan-Browning, D.Tsuchimoto, Y. Nakabeppu, C.E. Schrader, Apurinic/apyrimidinicendonuclease 2 is necessary for normal B cell development and recovery oflymphoid progenitors after chemotherapeutic challenge, J. Immunol. 186(2011) 1943–1950.

[247] S. Xanthoudakis, T. Curran, Redox regulation of AP-1: a link betweentranscription factor signaling and DNA repair, Adv. Exp. Med. Biol. 387(1996) 69–75.

[248] D.L. Ludwig, M.A. MacInnes, Y. Takiguchi, P.E. Purtymun, M. Henrie, M.Flannery, J. Meneses, R.A. Pedersen, D.J. Chen, A murine AP-endonucleasegene-targeted deficiency with post-implantation embryonic progression andionizing radiation sensitivity, Mutat. Res. 409 (1998) 17–29.

[249] L.B. Meira, S. Devaraj, G.E. Kisby, D.K. Burns, R.L. Daniel, R.E. Hammer, S.Grundy, I. Jialal, E.C. Friedberg, Heterozygosity for the mouse Apex generesults in phenotypes associated with oxidative stress, Cancer Res. 61 (2001)5552–5557.

[250] T. Izumi, D.B. Brown, C.V. Naidu, K.K. Bhakat, M.A. Macinnes, H. Saito, D.J.Chen, S. Mitra, Two essential but distinct functions of the mammalian abasicendonuclease, Proc. Natl. Acad. Sci. USA 102 (2005) 5739–5743.

[251] H. Fung, B. Demple, A vital role for Ape1/Ref1 protein in repairingspontaneous DNA damage in human cells, Mol. Cell 17 (2005) 463–470.

[252] J. Huamani, C.A. McMahan, D.C. Herbert, R. Reddick, J.R. McCarrey, M.I.MacInnes, D.J. Chen, C.A. Walter, Spontaneous mutagenesis is enhanced inApex heterozygous mice, Mol. Cell Biol. 24 (2004) 8145–8153.

[253] J.J. Raffoul, D.C. Cabelof, J. Nakamura, L.B. Meira, E.C. Friedberg, A.R. Heydari,Apurinic/apyrimidinic endonuclease (APE/REF-1) haploinsufficient micedisplay tissue-specific differences in DNA polymerase beta-dependent baseexcision repair, J. Biol. Chem. 279 (2004) 18425–18433.

[254] M. Huang, C.P. Dinney, X. Lin, J. Lin, H.B. Grossman, X. Wu, High-orderinteractions among genetic variants in DNA base excision repair pathwaygenes and smoking in bladder cancer susceptibility, Cancer Epidemiol.Biomarkers Prev. 16 (2007) 84–91.

[255] M. Wang, C. Qin, J. Zhu, L. Yuan, G. Fu, Z. Zhang, C. Yin, Genetic variants ofXRCC1, APE1, and ADPRT genes and risk of bladder cancer, DNA Cell Biol. 29(2010) 303–311.

[256] B. Agachan, O. Kucukhuseyin, P. Aksoy, A. Turna, I. Yaylim, U. Gormus, A.Ergen, U. Zeybek, B. Dalan, T. Isbir, Apurinic/apyrimidinic endonuclease(APE1) gene polymorphisms and lung cancer risk in relation to tobaccosmoking, Anticancer Res. 29 (2009) 2417–2420.

[257] C. Kiyohara, K. Takayama, Y. Nakanishi, Association of geneticpolymorphisms in the base excision repair pathway with lung cancer risk:a meta-analysis, Lung Cancer 54 (2006) 267–283.

[258] H. Kuasne, I.S. Rodrigues, R. Losi-Guembarovski, M.B. Reis, P.E. Fuganti, E.P.Gregorio, F. Libos Junior, H.M. Matsuda, M.A. Rodrigues, M.O. Kishima, I.M.Colus, Base excision repair genes XRCC1 and APEX1 and the risk for prostatecancer, Mol. Biol. Rep. 38 (2011) 1585–1591.

[259] E. Canbay, B. Agachan, M. Gulluoglu, T. Isbir, E. Balik, S. Yamaner, T. Bulut, C.Cacina, I.Y. Eraltan, A. Yilmaz, D. Bugra, Possible associations of APE1polymorphism with susceptibility and HOGG1 polymorphism withprognosis in gastric cancer, Anticancer Res. 30 (2010) 1359–1364.

[260] J.J. Hu, T.R. Smith, M.S. Miller, K. Lohman, L.D. Case, Genetic regulation ofionizing radiation sensitivity and breast cancer risk, Environ. Mol. Mutagen39 (2002) 208–215.

[261] Y. Zhang, P.A. Newcomb, K.M. Egan, L. Titus-Ernstoff, S. Chanock, R. Welch,L.A. Brinton, J. Lissowska, A. Bardin-Mikolajczak, B. Peplonska, N. Szeszenia-Dabrowska, W. Zatonski, M. Garcia-Closas, Genetic polymorphisms in base-excision repair pathway genes and risk of breast cancer, Cancer Epidemiol.Biomarkers Prev. 15 (2006) 353–358.

[262] D.F. Easton, K.A. Pooley, A.M. Dunning, P.D. Pharoah, D. Thompson, D.G.Ballinger, J.P. Struewing, J. Morrison, H. Field, R. Luben, N. Wareham, S.Ahmed, C.S. Healey, R. Bowman, K.B. Meyer, C.A. Haiman, L.K. Kolonel, B.E.Henderson, L. Le Marchand, P. Brennan, S. Sangrajrang, V. Gaborieau, F.Odefrey, C.Y. Shen, P.E. Wu, H.C. Wang, D. Eccles, D.G. Evans, J. Peto, O.Fletcher, N. Johnson, S. Seal, M.R. Stratton, N. Rahman, G. Chenevix-Trench,S.E. Bojesen, B.G. Nordestgaard, C.K. Axelsson, M. Garcia-Closas, L. Brinton, S.Chanock, J. Lissowska, B. Peplonska, H. Nevanlinna, R. Fagerholm, H. Eerola, D.Kang, K.Y. Yoo, D.Y. Noh, S.H. Ahn, D.J. Hunter, S.E. Hankinson, D.G. Cox, P.Hall, S. Wedren, J. Liu, Y.L. Low, N. Bogdanova, P. Schurmann, T. Dork, R.A.Tollenaar, C.E. Jacobi, P. Devilee, J.G. Klijn, A.J. Sigurdson, M.M. Doody, B.H.Alexander, J. Zhang, A. Cox, I.W. Brock, G. MacPherson, M.W. Reed, F.J. Couch,E.L. Goode, J.E. Olson, H. Meijers-Heijboer, A. van den Ouweland, A.



Uitterlinden, F. Rivadeneira, R.L. Milne, G. Ribas, A. Gonzalez-Neira, J. Benitez,J.L. Hopper, M. McCredie, M. Southey, G.G. Giles, C. Schroen, C. Justenhoven,H. Brauch, U. Hamann, Y.D. Ko, A.B. Spurdle, J. Beesley, X. Chen, A.Mannermaa, V.M. Kosma, V. Kataja, J. Hartikainen, N.E. Day, D.R. Cox, B.A.Ponder, Genome-wide association study identifies novel breast cancersusceptibility loci, Nature 447 (2007) 1087–1093.

[263] G. Thomas, K.B. Jacobs, P. Kraft, M. Yeager, S. Wacholder, D.G. Cox, S.E.Hankinson, A. Hutchinson, Z. Wang, K. Yu, N. Chatterjee, M. Garcia-Closas, J.Gonzalez-Bosquet, L. Prokunina-Olsson, N. Orr, W.C. Willett, G.A. Colditz, R.G.Ziegler, C.D. Berg, S.S. Buys, C.A. McCarty, H.S. Feigelson, E.E. Calle, M.J. Thun,R. Diver, R. Prentice, R. Jackson, C. Kooperberg, R. Chlebowski, J. Lissowska, B.Peplonska, L.A. Brinton, A. Sigurdson, M. Doody, P. Bhatti, B.H. Alexander, J.Buring, I.M. Lee, L.J. Vatten, K. Hveem, M. Kumle, R.B. Hayes, M. Tucker, D.S.Gerhard, J.F. Fraumeni Jr., R.N. Hoover, S.J. Chanock, D.J. Hunter, A multistagegenome-wide association study in breast cancer identifies two new riskalleles at 1p11.2 and 14q24.1 (RAD51L1), Nat. Genet. 41 (2009) 579–584.

[264] C. Turnbull, S. Ahmed, J. Morrison, D. Pernet, A. Renwick, M. Maranian, S. Seal,M. Ghoussaini, S. Hines, C.S. Healey, D. Hughes, M. Warren-Perry, W. Tapper,D. Eccles, D.G. Evans, M. Hooning, M. Schutte, A. van den Ouweland, R.Houlston, G. Ross, C. Langford, P.D. Pharoah, M.R. Stratton, A.M. Dunning, N.Rahman, D.F. Easton, Genome-wide association study identifies five newbreast cancer susceptibility loci, Nat. Genet. 42 (2010) 504–507.

[265] D. Gu, M. Wang, Z. Zhang, J. Chen, The DNA repair gene APE1 T1349Gpolymorphism and cancer risk: a meta-analysis of 27 case-control studies,Mutagenesis 24 (2009) 507–512.

[266] M.Z. Hadi, M.A. Coleman, K. Fidelis, H.W. Mohrenweiser, D.M. Wilson 3rd,Functional characterization of Ape1 variants identified in the humanpopulation, Nucleic Acids Res. 28 (2000) 3871–3879.

[267] S. Daviet, S. Couve-Privat, L. Gros, K. Shinozuka, H. Ide, M. Saparbaev, A.A.Ishchenko, Major oxidative products of cytosine are substrates for thenucleotide incision repair pathway, DNA Repair (Amst.) 6 (2007) 8–18.

[268] M. Pieretti, N.H. Khattar, S.A. Smith, Common polymorphisms and somaticmutations in human base excision repair genes in ovarian and endometrialcancers, Mutat. Res. 432 (2001) 53–59.

[269] T.A. Kunkel, The mutational specificity of DNA polymerase-beta duringin vitro DNA synthesis. Production of frameshift, base substitution, anddeletion mutations, J. Biol. Chem. 260 (1985) 5787–5796.

[270] R. Prasad, W.A. Beard, J.Y. Chyan, M.W. Maciejewski, G.P. Mullen, S.H. Wilson,Functional analysis of the amino-terminal 8-kDa domain of DNA polymerasebeta as revealed by site-directed mutagenesis. DNA binding and 50-deoxyribose phosphate lyase activities, J. Biol. Chem. 273 (1998) 11121–11126.

[271] R.W. Sobol, R. Prasad, A. Evenski, A. Baker, X.P. Yang, J.K. Horton, S.H. Wilson,The lyase activity of the DNA repair protein beta-polymerase protects fromDNA-damage-induced cytotoxicity, Nature 405 (2000) 807–810.

[272] H. Pelletier, M.R. Sawaya, A. Kumar, S.H. Wilson, J. Kraut, Structures of ternarycomplexes of rat DNA polymerase beta, a DNA template-primer, and ddCTP,Science 264 (1994) 1891–1903.

[273] W.A. Beard, R. Prasad, S.H. Wilson, Activities and mechanism of DNApolymerase beta, Methods Enzymol. 408 (2006) 91–107.

[274] V.K. Batra, W.A. Beard, E.W. Hou, L.C. Pedersen, R. Prasad, S.H. Wilson,Mutagenic conformation of 8-oxo-7,8-dihydro-20-dGTP in the confines of aDNA polymerase active site, Nat. Struct. Mol. Biol. 17 (2010) 889–890.

[275] N.A. Cavanaugh, W.A. Beard, S.H. Wilson, DNA polymerase betaribonucleotide discrimination: insertion, misinsertion, extension, andcoding, J. Biol. Chem. 285 (2010) 24457–24465.

[276] N.A. Cavanaugh, W.A. Beard, V.K. Batra, L. Perera, L.G. Pedersen, S.H. Wilson,Molecular insights into DNA polymerase deterrents for ribonucleotideinsertion, J. Biol. Chem. 286 (2011) 31650–31660.

[277] V.K. Batra, W.A. Beard, D.D. Shock, L.C. Pedersen, S.H. Wilson, Structures ofDNA polymerase beta with active-site mismatches suggest a transient abasicsite intermediate during misincorporation, Mol. Cell 30 (2008) 315–324.

[278] W.A. Beard, D.D. Shock, V.K. Batra, L.C. Pedersen, S.H. Wilson, DNApolymerase beta substrate specificity: side chain modulation of the ‘‘A-rule’’, J. Biol. Chem. 284 (2009) 31680–31689.

[279] J. Yamtich, D. Starcevic, J. Lauper, E. Smith, I. Shi, S. Rangarajan, J. Jaeger, J.B.Sweasy, Hinge residue I174 is critical for proper dNTP selection by DNApolymerase beta, Biochemistry 49 (2010) 2326–2334.

[280] G.C. Lin, J. Jaeger, K.A. Eckert, J.B. Sweasy, Loop II of DNA polymerase beta isimportant for discrimination during substrate binding, DNA Repair (Amst.) 8(2009) 182–189.

[281] J. Yamtich, W.C. Speed, E. Straka, J.R. Kidd, J.B. Sweasy, K.K. Kidd, Population-specific variation in haplotype composition and heterozygosity at the POLBlocus, DNA Repair (Amst.) 8 (2009) 579–584.

[282] H. Gu, J.D. Marth, P.C. Orban, H. Mossmann, K. Rajewsky, Deletion of a DNApolymerase beta gene segment in T cells using cell type-specific genetargeting, Science 265 (1994) 103–106.

[283] N. Sugo, Y. Aratani, Y. Nagashima, Y. Kubota, H. Koyama, Neonatal lethalitywith abnormal neurogenesis in mice deficient in DNA polymerase beta,EMBO J. 19 (2000) 1397–1404.

[284] D.C. Cabelof, Z. Guo, J.J. Raffoul, R.W. Sobol, S.H. Wilson, A. Richardson, A.R.Heydari, Base excision repair deficiency caused by polymerase betahaploinsufficiency: accelerated DNA damage and increased mutationalresponse to carcinogens, Cancer Res. 63 (2003) 5799–5807.

[285] Z. Guo, L. Zheng, H. Dai, M. Zhou, H. Xu, B. Shen, Human DNA polymerase betapolymorphism, Arg137Gln, impairs its polymerase activity and interaction

with PCNA and the cellular base excision repair capacity, Nucleic Acids Res.37 (2009) 3431–3441.

[286] A. Matakidou, R. el Galta, E.L. Webb, M.F. Rudd, H. Bridle, T. Eisen, R.S.Houlston, Genetic variation in the DNA repair genes is predictive of outcomein lung cancer, Hum. Mol. Genet. 16 (2007) 2333–2340.

[287] D. Starcevic, S. Dalal, J.B. Sweasy, Is there a link between DNA polymerasebeta and cancer?, Cell Cycle 3 (2004) 998–1001

[288] T. Lang, M. Maitra, D. Starcevic, S.X. Li, J.B. Sweasy, A DNA polymerase betamutant from colon cancer cells induces mutations, Proc. Natl. Acad. Sci. USA101 (2004) 6074–6079.

[289] S. Dalal, S. Hile, K.A. Eckert, K.W. Sun, D. Starcevic, J.B. Sweasy, Prostate-cancer-associated I260M variant of DNA polymerase beta is a sequence-specific mutator, Biochemistry 44 (2005) 15664–15673.

[290] T. Lang, S. Dalal, A. Chikova, D. DiMaio, J.B. Sweasy, The E295K DNApolymerase beta gastric cancer-associated variant interferes with baseexcision repair and induces cellular transformation, Mol. Cell Biol. 27(2007) 5587–5596.

[291] S. Dalal, A. Chikova, J. Jaeger, J.B. Sweasy, The Leu22Pro tumor-associatedvariant of DNA polymerase beta is dRP lyase deficient, Nucleic Acids Res. 36(2008) 411–422.

[292] J.B. Sweasy, T. Lang, D. Starcevic, K.W. Sun, C.C. Lai, D. Dimaio, S. Dalal,Expression of DNA polymerase {beta} cancer-associated variants in mousecells results in cellular transformation, Proc. Natl. Acad. Sci. USA 102 (2005)14350–14355.

[293] D.K. Srivastava, I. Husain, C.L. Arteaga, S.H. Wilson, DNA polymerase betaexpression differences in selected human tumors and cell lines,Carcinogenesis 20 (1999) 1049–1054.

[294] V. Bergoglio, M.J. Pillaire, M. Lacroix-Triki, B. Raynaud-Messina, Y. Canitrot, A.Bieth, M. Gares, M. Wright, G. Delsol, L.A. Loeb, C. Cazaux, J.S. Hoffmann,Deregulated DNA polymerase beta induces chromosome instability andtumorigenesis, Cancer Res. 62 (2002) 3511–3514.

[295] Y. Canitrot, J.P. Capp, N. Puget, A. Bieth, B. Lopez, J.S. Hoffmann, C. Cazaux,DNA polymerase beta overexpression stimulates the Rad51-dependenthomologous recombination in mammalian cells, Nucleic Acids Res. 32(2004) 5104–5112.

[296] K. Yoshizawa, E. Jelezcova, A.R. Brown, J.F. Foley, A. Nyska, X. Cui, L.J. Hofseth,R.M. Maronpot, S.H. Wilson, A.R. Sepulveda, R.W. Sobol, Gastrointestinalhyperplasia with altered expression of DNA polymerase beta, PLoS One 4(2009) e6493.

[297] B.J. Glassner, L.J. Rasmussen, M.T. Najarian, L.M. Posnick, L.D. Samson,Generation of a strong mutator phenotype in yeast by imbalanced baseexcision repair, Proc. Natl. Acad. Sci. USA 95 (1998) 9997–10002.

[298] Z. Dong, A.E. Tomkinson, ATM mediates oxidative stress-induceddephosphorylation of DNA ligase IIIalpha, Nucleic Acids Res. 34 (2006).5721-5279.

[299] I.D. Odell, J.E. Barbour, D.L. Murphy, J.A. Della Maria, J.B. Sweasy, A.E.Tomkinson, S.S. Wallace, D.S. Pederson, Nucleosome disruption by DNA ligaseIII-XRCC1 promotes efficient base excision repair, Mol. Cell Biol. (2011).

[300] N. Puebla-Osorio, D.B. Lacey, F.W. Alt, C. Zhu, Early embryonic lethality due totargeted inactivation of DNA ligase III, Mol. Cell Biol. 26 (2006) 3935–3941.

[301] D. Simsek, A. Furda, Y. Gao, J. Artus, E. Brunet, A.K. Hadjantonakis, B. VanHouten, S. Shuman, P.J. McKinnon, M. Jasin, Crucial role for DNA ligase III inmitochondria but not in Xrcc1-dependent repair, Nature 471 (2011) 245–248.

[302] K.W. Caldecott, XRCC1 and DNA strand break repair, DNA Repair (Amst.) 2(2003) 955–969.

[303] D. Simsek, E. Brunet, S.Y. Wong, S. Katyal, Y. Gao, P.J. McKinnon, J. Lou, L.Zhang, J. Li, E.J. Rebar, P.D. Gregory, M.C. Holmes, M. Jasin, DNA ligase IIIpromotes alternative nonhomologous end-joining during chromosomaltranslocation formation, PLoS Genet. 7 (2011) e1002080.

[304] J. Della-Maria, Y. Zhou, M.S. Tsai, J. Kuhnlein, J.P. Carney, T.T. Paull, A.E.Tomkinson, Human Mre11/Human Rad50/Nbs1 and DNA ligase III{alpha}/XRCC1 protein complexes act together in an alternative nonhomologous endjoining pathway, J. Biol. Chem. 286 (2011) 33845–33853.

[305] C. Breslin, K.W. Caldecott, DNA 30-phosphatase activity is critical for rapidglobal rates of single-strand break repair following oxidative stress, Mol. CellBiol. 29 (2009) 4653–4662.

[306] M. Akbari, K. Solvang-Garten, A. Hanssen-Bauer, N.V. Lieske, H.S. Pettersen,G.K. Pettersen, D.M. Wilson 3rd, H.E. Krokan, M. Otterlei, Direct interactionbetween XRCC1 and UNG2 facilitates rapid repair of uracil in DNA by XRCC1complexes, DNA Repair (Amst.) 9 (2010) 785–795.

[307] N. Levy, M. Oehlmann, F. Delalande, H.P. Nasheuer, A. Van Dorsselaer, V.Schreiber, G. de Murcia, J. Menissier-de Murcia, D. Maiorano, A. Bresson,XRCC1 interacts with the p58 subunit of DNA Pol alpha-primase and maycoordinate DNA repair and replication during S phase, Nucleic Acids Res. 37(2009) 3177–3188.

[308] A.E. Vidal, S. Boiteux, I.D. Hickson, J.P. Radicella, XRCC1 coordinates the initialand late stages of DNA abasic site repair through protein–proteininteractions, EMBO J. 20 (2001) 6530–6539.

[309] T. Yamamori, J. DeRicco, A. Naqvi, T.A. Hoffman, I. Mattagajasingh, K. Kasuno,S.B. Jung, C.S. Kim, K. Irani, SIRT1 deacetylates APE1 and regulates cellularbase excision repair, Nucleic Acids Res. 38 (2010) 832–845.

[310] R.S. Tebbs, M.L. Flannery, J.J. Meneses, A. Hartmann, J.D. Tucker, L.H.Thompson, J.E. Cleaver, R.A. Pedersen, Requirement for the Xrcc1 DNA baseexcision repair gene during early mouse development, Dev. Biol. 208 (1999)513–529.



[311] D.R. McNeill, P.C. Lin, M.G. Miller, P.J. Pistell, N.C. de Souza-Pinto, K.W.Fishbein, R.G. Spencer, Y. Liu, C. Pettan-Brewer, W.C. Ladiges, D.M. Wilson3rd, XRCC1 haploinsufficiency in mice has little effect on aging, but adverselymodifies exposure-dependent susceptibility, Nucleic Acids Res. (2011).

[312] L.H. Thompson, K.W. Brookman, L.E. Dillehay, A.V. Carrano, J.A. Mazrimas, C.L.Mooney, J.L. Minkler, A CHO-cell strain having hypersensitivity to mutagens,a defect in DNA strand-break repair, and an extraordinary baseline frequencyof sister-chromatid exchange, Mutat. Res. 95 (1982) 427–440.

[313] L.H. Thompson, K.W. Brookman, N.J. Jones, S.A. Allen, A.V. Carrano, Molecularcloning of the human XRCC1 gene, which corrects defective DNA strand breakrepair and sister chromatid exchange, Mol. Cell Biol. 10 (1990) 6160–6171.

[314] B.R. Berquist, D.K. Singh, J. Fan, D. Kim, E. Gillenwater, A. Kulkarni, V.A. Bohr,E.J. Ackerman, A.E. Tomkinson, D.M. Wilson 3rd, Functional capacity of XRCC1protein variants identified in DNA repair-deficient Chinese hamster ovary celllines and the human population, Nucleic Acids Res. 38 (2010) 5023–5035.

[315] G. Ginsberg, K. Angle, K. Guyton, B. Sonawane, Polymorphism in the DNArepair enzyme XRCC1: utility of current database and implications for humanhealth risk assessment, Mutat. Res. 727 (2011) 1–15.

[316] A. Roszak, M. Lianeri, P.P. Jagodzinski, Involvement of the XRCC1 Arg399Glngene polymorphism in the development of cervical carcinoma, Int. J. Biol.Markers (2011).

[317] G. Barbisan, L.O. Perez, L. Difranza, C.J. Fernandez, N.E. Ciancio, C.D. Golijow,XRCC1 Arg399Gln polymorphism and risk for cervical cancer development inArgentine women, Eur. J. Gynaecol. Oncol. 32 (2011) 274–279.

[318] J. Geng, Q. Zhang, C. Zhu, J. Wang, L. Chen, XRCC1 genetic polymorphismArg399Gln and prostate cancer risk: a meta-analysis, Urology 74 (2009) 648–653.

[319] B. Wei, Y. Zhou, Z. Xu, J. Ruan, M. Zhu, K. Jin, D. Zhou, Q. Hu, Q. Wang, Z. Wang,Z. Yan, XRCC1 Arg399Gln and Arg194Trp polymorphisms in prostate cancerrisk: a meta-analysis, Prostate Cancer Prostatic. Dis. 14 (2011) 225–231.

[320] M.R. Roberts, P.G. Shields, C.B. Ambrosone, J. Nie, C. Marian, S.S. Krishnan, D.S.Goerlitz, R. Modali, M. Seddon, T. Lehman, K.L. Amend, M. Trevisan, S.B. Edge,J.L. Freudenheim, Single-nucleotide polymorphisms in DNA repair genes andassociation with breast cancer risk in the web study, Carcinogenesis 32(2011) 1223–1230.

[321] R.A. Ryu, K. Tae, H.J. Min, J.H. Jeong, S.H. Cho, S.H. Lee, Y.H. Ahn, XRCC1polymorphisms and risk of papillary thyroid carcinoma in a Korean sample, J.Korean Med. Sci. 26 (2011) 991–995.

[322] F.Y. Chiang, C.W. Wu, P.J. Hsiao, W.R. Kuo, K.W. Lee, J.C. Lin, Y.C. Liao, S.H. Juo,Association between polymorphisms in DNA base excision repair genesXRCC1, APE1, and ADPRT and differentiated thyroid carcinoma, Clin. CancerRes. 14 (2008) 5919–5924.

[323] H. Xue, P. Ni, B. Lin, H. Xu, G. Huang, X-ray repair cross-complementing group1 (XRCC1) genetic polymorphisms and gastric cancer risk: a HuGE review andmeta-analysis, Am. J. Epidemiol. 173 (2011) 363–375.

[324] P. Vodicka, R. Stetina, V. Polakova, E. Tulupova, A. Naccarati, L. Vodickova, R.Kumar, M. Hanova, B. Pardini, J. Slyskova, L. Musak, G. De Palma, P. Soucek, K.Hemminki, Association of DNA repair polymorphisms with DNA repairfunctional outcomes in healthy human subjects, Carcinogenesis 28 (2007)657–664.

[325] E. Halasova, T. Matakova, L. Musak, V. Polakova, L. Letkova, D. Dobrota, P.Vodicka, Evaluating chromosomal damage in workers exposed to hexavalentchromium and the modulating role of polymorphisms of DNA repair genes,Int. Arch. Occup. Environ. Health (2011).

[326] R. Chandirasekar, K. Suresh, R. Jayakumar, R. Venkatesan, B. LakshmanKumar, K. Sasikala, XRCC1 gene variants and possible links with chromosomeaberrations and micronucleus in active and passive smokers, Environ.Toxicol. Pharmacol. 32 (2011) 185–192.

[327] D. Li, Q. Zhou, Y. Liu, Y. Yang, Q. Li, DNA repair gene polymorphism associatedwith sensitivity of lung cancer to therapy, Med. Oncol. (2011).

[328] S.H. Berger, D.L. Pittman, M.D. Wyatt, Uracil in DNA: consequences forcarcinogenesis and chemotherapy, Biochem. Pharmacol. 76 (2008) 697–706.

[329] S.X. Li, A. Sjolund, L. Harris, J.B. Sweasy, DNA repair and personalized breastcancer therapy, Environ. Mol. Mutagen. 51 (2010) 897–908.

[330] G. Tell, D.M. Wilson 3rd, Targeting DNA repair proteins for cancer treatment,Cell Mol. Life Sci. 67 (2010) 3569–3572.

[331] L. Tentori, L. Orlando, P.M. Lacal, E. Benincasa, I. Faraoni, E. Bonmassar, S.D’Atri, G. Graziani, Inhibition of O6-alkylguanine DNA-alkyltransferase orpoly(ADP-ribose) polymerase increases susceptibility of leukemic cells toapoptosis induced by temozolomide, Mol. Pharmacol. 52 (1997) 249–258.

[332] R.N. Trivedi, X.H. Wang, E. Jelezcova, E.M. Goellner, J.B. Tang, R.W. Sobol,Human methyl purine DNA glycosylase and DNA polymerase beta expressioncollectively predict sensitivity to temozolomide, Mol. Pharmacol. 74 (2008)505–516.

[333] J.B. Tang, D. Svilar, R.N. Trivedi, X.H. Wang, E.M. Goellner, B. Moore, R.L.Hamilton, L.A. Banze, A.R. Brown, R.W. Sobol, N-methylpurine DNAglycosylase and DNA polymerase beta modulate BER inhibitor potentiationof glioma cells to temozolomide, Neuro Oncol. 13 (2011) 471–486.

[334] E.M. Goellner, B. Grimme, A.R. Brown, Y.C. Lin, X.H. Wang, K.F. Sugrue, L.Mitchell, R.N. Trivedi, J.B. Tang, R.W. Sobol, Overcoming temozolomideresistance in glioblastoma via dual inhibition of NAD+ biosynthesis and baseexcision repair, Cancer Res. 71 (2011) 2308–2317.

[335] M.Z. Mohammed, V.N. Vyjayanti, C.A. Laughton, L.V. Dekker, P.M. Fischer,D.M. Wilson 3rd, R. Abbotts, S. Shah, P.M. Patel, I.D. Hickson, S. Madhusudan,Development and evaluation of human AP endonuclease inhibitors inmelanoma and glioma cell lines, Br. J. Cancer. 104 (2011) 653–663.

[336] A. Simeonov, A. Kulkarni, D. Dorjsuren, A. Jadhav, M. Shen, D.R. McNeill, C.P.Austin, D.M. Wilson 3rd, Identification and characterization of inhibitors ofhuman apurinic/apyrimidinic endonuclease APE1, PLoS One 4 (2009) e5740.

[337] G. Tell, D. Fantini, F. Quadrifoglio, Understanding different functions ofmammalian AP endonuclease (APE1) as a promising tool for cancertreatment, Cell Mol. Life Sci. 67 (2010) 3589–3608.

[338] D.M. Wilson 3rd, A. Simeonov, Small molecule inhibitors of DNA repairnuclease activities of APE1, Cell Mol. Life Sci. 67 (2010) 3621–3631.

[339] G.C. Stachelek, S. Dalal, K.A. Donigan, D. Campisi Hegan, J.B. Sweasy, P.M.Glazer, Potentiation of temozolomide cytotoxicity by inhibition of DNApolymerase beta is accentuated by BRCA2 mutation, Cancer Res. 70 (2010)409–417.

[340] T. Helleday, The underlying mechanism for the PARP and BRCA syntheticlethality: clearing up the misunderstandings, Mol. Oncol. 5 (2011) 387–393.

[341] J.K. Horton, S.H. Wilson, Hypersensitivity phenotypes associated with geneticand synthetic inhibitor-induced base excision repair deficiency, DNA Repair(Amst.) 6 (2007) 530–543.

[342] E. Jelezcova, R.N. Trivedi, X.H. Wang, J.B. Tang, A.R. Brown, E.M. Goellner, S.Schamus, J.L. Fornsaglio, R.W. Sobol, Parp1 activation in mouse embryonicfibroblasts promotes Pol beta-dependent cellular hypersensitivity toalkylation damage, Mutat. Res. 686 (2010) 57–67.

[343] C.A. Sucato, T.G. Upton, B.A. Kashemirov, J. Osuna, K. Oertell, W.A. Beard, S.H.Wilson, J. Florian, A. Warshel, C.E. McKenna, M.F. Goodman, DNA polymerasebeta fidelity: halomethylene-modified leaving groups in pre-steady-statekinetic analysis reveal differences at the chemical transition state,Biochemistry 47 (2008) 870–879.

[344] C.E. McKenna, B.A. Kashemirov, L.W. Peterson, M.F. Goodman, Modificationsto the dNTP triphosphate moiety: from mechanistic probes for DNApolymerases to antiviral and anti-cancer drug design, Biochim. Biophys.Acta 1804 (2010) 1223–1230.

[345] X. Chen, S. Zhong, X. Zhu, B. Dziegielewska, T. Ellenberger, G.M. Wilson, A.D.MacKerell Jr., A.E. Tomkinson, Rational design of human DNA ligase inhibitorsthat target cellular DNA replication and repair, Cancer Res. 68 (2008) 3169–3177.

[346] S. Zhong, X. Chen, X. Zhu, B. Dziegielewska, K.E. Bachman, T. Ellenberger, J.D.Ballin, G.M. Wilson, A.E. Tomkinson, A.D. MacKerell Jr., Identification andvalidation of human DNA ligase inhibitors using computer-aided drug design,J. Med. Chem. 51 (2008) 4553–4562.



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