DNA Repair and Cancer

Genome Instability

Science, 26 July 2002, p. 544

Hoeijmakers, Nature 01

Damage tolerance

Hoeijmakers, Nature 01

Translesion synthesis

Syndrome Cancer Risk Defective repair process

Xeroderma pigmentosum

Skin NER, damage bypass*

Hereditary non-polyposis colorectal cancer

Colorectal cancer MMR, BER*

BRCA1/BRCA2 Breast/Ovarian cancer Homologous recombination (HR)

Fanconi Anemia Leukemia, others Crosslink repair

Cockayne None Transcription coupled

Trichothiodystrophy None Transcription coupled

Ataxia telangiectasia Lymphomas Double strand break

Nijmegan breakage Lymphomas Double strand break

Werner Various, aging Not definitive

Bloom Leukemia, lymphoma Likely HR

Genome instability syndromes

Major DNA repair pathways:

Nucleotide excision repair (NER)-- deals with broadclass of helix –distorting lesions that disrupttranscription and replication

Base excision repair (BER)-- deals with small chemical alterations of bases. Particularly relevant for preventing mutation.

Double-strand break (DSB) repair—Homologousrecombination (HR) and Nonhomologous end-joining(NHEJ)

Mismatch repair (MMR)– corrects replicationerrors, and can repair alkylated bases.

http://www.rndsystems.com/mini_review_detail_objectname_MR03_DNADamageResponse.aspx

NER

Global genome

Transcription-Coupled Repair(TCR)

Xeroderma Pigmentosum (XP)

Cockayne Syndrome

Trichothiodystrophy

Xeroderma Pigmentosum

• Clinical symptoms:– Early onset severe photosensitivity to UV exposure– Highly elevated risk of skin cancer (median age of onset is

8, compared to almost 60 for the rest of us)– Ocular abnormalities– Varying severity of neurological abnormalities in some

but not all patients

• Clinical subtypes – Complementation groups A through G, and XP-V

Xeroderma Pigmentosum

• Cellular and Biochemical phenotypes:– Chromosomal abnormalities– Sensitivity to killing by DNA damaging agents– Defective nucleotide excision repair (NER)

• (seen in most but not all patients)

• Patients are assigned to ‘complementation groups’ based on cellular tests and genetic screens

XP-variant

BER

Association of cancer with alterations in pol betaAlso – defects in MUTYH predispose to colon cancer, G T transversions

Hoeijmakers, Nature 01

DSB Repair

HR- accurate,Primarily S/G2

NHEJ- error-pronePrimarily G1

Ataxia telangiectasiaATM

Nijmegan breakage syndrome NBS1

Breast cancerBRCA1 BRCA2

RAD51

Bloom syndromeBLM

Werner syndromeWRN

Fanconi anemia

BRCA1 and BRCA2• Breast cancer susceptibility genes

• Localize to sites of damage (damage foci)

• Both phosphorylated in response to damage

• Defects associated with breast and ovarian cancer

Venkitanaram, Cell 2002, 108, p. 171

two RAD51 sites also on C-terminus

a

b

c

e

d

f

gene conversion crossover

Fig. 1. HR repair of a DSB. See text at right for details.

BLM regulatesHJ resolution

Mismatch Repair

Hoeijmakers, Nature 01

www.nature.com/.../v21/n3/full/ng0399_247.html

Colorectal Cancer

• ~ 150K cases and 56K deaths every year from CRC• 90% of all cases are diagnosed in people 50 and older• Tell family and friends to get a colonoscopy at 50!!!!• Remaining 10% of cases (early onset) are mostly

associated with one of two genetic syndromes: – Familial adenomatous polyposis (FAP)

– Hereditary non-polyposis colorectal cancer (HNPCC)

HNPCC –caused by defects in MMR • Estimated to cause 1 to 5% of all CRC cases

– (not just CRC; stomach, ovary, endometrial, others )

• Criteria– At least 3 relatives in 2 generations diagnosed, at least one

diagnosed before the age of 50

– FAP excluded

• Lifetime risk of developing CRC is ~80% for patients– ~30% risk for endometrial, ~10 for ovarian and gastric

HNPCC • HNPCC tumors display a high frequency of DNA

microsatellite instability (“MSI” or “MIN” vs “CIN”)– Many mono, di, and trinucleotide repeats in genome

– HNPCC tumor DNA has a much higher number of changes in these simple repeated sequences

• Mismatch repair corrects errors caused by DNA polymerase ‘slippage’ events at repeat sequences

HNPCC • Mutations in MSH2 and MLH1 genes account for

>95% of all HNPCC cases• “MSH” = MutS homolog• “MLH” = MutL homolog• Mutations in other MMR genes are much rarer, but

have also been associated with HNPCC