FORUM EDITORIAL

DNA Repair Meets the RNA World

Chow H. Lee

Abstract

The ability to repair damaged DNA and to maintain genome stability is the utmost importance for the survival of anyspecies. Hence, it is not surprising to find that DNA repair mechanisms are evolutionarily conserved and are expectedto evolve to maintain the existence of species. In the last few years, there has been an exponential increase in theevidence linking RNA processing with DNA repair programs. For instance, the well-studied DNA base excisionrepair (BER) enzyme apurinic/apyrimidinic endonuclease 1 can cleave RNA molecules, regulate mRNA levels, andassociate physically with proteins involved in RNA processing. It is now clear that not only the expression ofnoncoding RNAs are changed uponDNAdamage, they canmodulate the expression of genes involved in the genomestability programs. The five reviews in this Forum provide the up-to-date knowledge on DNA repair, with a focus onBER, and a perspective on how the two ancient biochemical pathways are linked. The contributions demonstrate thecomplexity of such interactions, but also pointed out the opportunities for new therapeutic interventions. Futurein vivo studies on the link between DNA repair processes and RNA metabolism should contribute to our basicunderstanding of physiology, disease, and treatment strategies. Antioxid. Redox Signal. 20, 618620.

Introduction

Whenever I teachmy undergraduate students topics innucleic acids, I often stress the differences betweenDNA and RNA molecules. RNA is made of uracil instead ofthymine in DNA and which has an additional methyl group atits C5 position of the base and therefore thymine is sometimeknown as 5-methyl uracil. In addition, RNA has a hydroxylgroup at C2 position of its sugar molecule, whereas thesugar moiety in DNA lacks such hydroxyl groups. Suchsubtle differences contribute to the differences in thechemistry and structure of DNA and RNA. Based on in-formation in the textbook, we also teach students that thereare specific enzymes and proteins involved in DNA me-tabolism such as DNA repair, and then, there are otherspecific enzymes and proteins involved in RNA metabo-lism. Findings in the last few years on the enzymes andpathways of DNA repair have now confirmed that this is notthe case. The processes of DNA repair and RNAmetabolismare more intimate than we previously thought. Two recentreviews have dealt on specific topics in this field (5, 7). ThisForum aims to provide up-to-date information in the field ofDNA repair, particularly on base excision repair (BER), anda perspective on how DNA repair mechanism and RNA

metabolism, the two ancient biochemical pathways, arelinked (Fig. 1).

Oxidative Damage and BER

First, the review by Scott et al. (6) provides an overview ofthe DNA repair pathways. The role of reactive oxygen spe-cies in DNA damage and its link to cancer formation wasnicely discussed. The review then focuses on the BERpathway, providing a historical look at the development ofthe field, and then, the detailed steps in BER with the mostupdated information. The most studied base damage 8-hydroxyguanine and the enzymes responsible for its repairwere also discussed. Finally, Scott et al. (6) briefly discussedone of the most studied BER enzymes, apurinic/apyrimidinicendonuclease 1 (APE1). APE1s multiple activities, subcel-lular localization, and links with cancer were summarized,which very nicely take us into the next review, which isentirely devoted to this very important enzyme.

The Human APE1

Li and Wilson (3) provide a comprehensive review andrecent findings on the human APE1. A short history on the

Chemistry Program, University of Northern British Columbia, Prince George, Canada.

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discovery of the enzyme, its sequence, and structural simi-larities to its orthologues, including Exonuclease III fromEscherichia coli, were presented. The authors discuss all theknown biochemical activities of APE1, including its mostrecently discovered ability to cleave RNA species. Evidencefor the various significant biological roles of APE1, includingthose in the cytoplasm and mitochondria, was also discussed.The review then describes the possible link between APE1and human diseases such as cancer and neurological diseases,focusing on the possible contribution of APE1 variants. Fi-nally, Li and Wilson (3) discuss the current and futurestrategies in targeting APE1 for therapeutic purposes. Inter-estingly, another BER enzyme SMUG1 has recentlybeen shown to cleave single-stranded RNA and physicallyassociate with DKC1, a ribosomal RNA processing pro-tein (2). More surprisingly, the SMUG1/DKC1 interactiontargets the complex to nucleoli contributing to ribosomalRNA quality control (2), a feat that is remarkably similar toAPE1 (1).

Roles of the Nucleolus in DNA Damage Response

The review by Antonialli et al. (1) discusses the evidencefor the roles of the nucleolus in regulating DNA damageresponse (DDR). The authors first provide an overview onRNA oxidative damages followed by description of thestructure, composition, and known functions of the nucleolus,namely, in the processing of ribosomal RNAs. It is proposedthat some proteins contain nucleolar localization sequences,and the nucleolus serves as a storage organelle for manynuclear proteins, including proteins involved in DNA repair.The authors discuss the interaction between APE1 and thehub protein in the nucleolus, nucleophosmin, as an examplewhereby the nucleolus may serve as a hub for the repair ofoxidatively damaged RNA upon stress. Last, it is proposedthat some proteins evolve to possess an unfolded protein

domain such as those found at the N-terminus of APE1. Theauthors discuss that such domain is important for biomolec-ular interactions and could serve as a novel target for thera-peutic purposes.

Post-Transcriptional Regulation of DDR

The review by McKay (4) describes the significant roleplayed by mRNA stability in the regulation of DDR. McKayfirst discusses the evidence that, ultraviolet light can lead toinhibition of the synthesis and processing of transcripts. Thereview briefly describes the many cellular pathways acti-vated upon DNA damage, including the p53-dependent and-independent transcriptional mechanisms. McKay then dis-cusses the significance of the mRNA stability pathway incircumventing the transcriptional inhibition imposed uponDNA damage. Several p53-responsive mRNAs contain se-quences at their 3-untranslated region that can destabilizetheir transcripts, supporting the evidence that transcriptionandmRNA stability regulation are closely linked. The reviewalso discusses the evidence that ultraviolet light can lead toincreased stability of mRNAs as well as accelerated decay ofother sets of mRNAs.

Noncoding RNAs in DNA Repair

Finally, the review by Wan et al. (8) discusses theemerging roles of noncoding RNAs (ncRNAs) in DNA repairand genome integrity. The authors provided many examplesof microRNAs and long ncRNAs regulating the key genes inDDR and reactive oxygen species signaling pathways. Thereview also discusses the potential roles of other smallncRNAs in regulating DDR. In addition, the expressionprofiles of ncRNAs are itself modulated upon DNA damage.The authors discuss the evidence that both the transcriptionaland post-transcriptional mechanisms of ncRNAs are modu-lated. Wan et al. (8) propose and discuss that ncRNAs

FIG. 1. The link between DNArepair and RNA metabolism. Theschematic diagram provides anoverview on how components inthe DNA repair and RNA metabo-lism are bridged as referred to inthe Forum contributions. The criti-cal issues are whether these inter-actions have implications for ourunderstanding on the physiology,pathology, and disease treatmentstrategies. To see this illustration incolor, the reader is referred to theweb version of this article at www.liebertpub.com/ars

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involved in the DDR could serve as diagnostic biomarkersand therapeutic targets.

Summary

This Forum illustrates the progress and critical issues inour understanding of DNA repair mechanisms, particularlyon the BER pathway. The discovery of DNA repair proteinssuch as APE1 and SMUG1 to have a role in RNAmetabolismand the increasing evidence for the role of ncRNAs in theregulation of DNA repair processes have added the unex-pected complexities, but at the same time offer unique op-portunities for new therapeutic intervention. I believe that inthe near future, there will be more surprising findings, whichwill reveal the unexpected link between DNA repair mech-anisms and RNA metabolism. Would such an understandingat the molecular level lead to new insights into physiology,disease, and treatment strategies? These are the challengingquestions that need to be addressed.

Acknowledgment

The author thanks the Natural Sciences and EngineeringResearch Council (#227158) for their continuous financialsupport.

References

1. Antonialli G, Lirussi L, Poletto M, and Tell G. Emergingroles of the nucleolus in regulating the DNA damage re-sponse: the noncanonical DNA repair enzyme APE1/Ref-1as a paradigmatical example. Antioxid Redox Signal 20:621639, 2014.

2. Jobert L, Skjeldam HK, Dalhus B, Galashevskaya A, VagboCB, Bjoras M, and Nilsen H. The human base excision repairenzyme SMUG1 directly interacts with DKC1 and contrib-utes to RNA quality control. Mol Cell 49: 330345, 2013.

3. Li M and Wilson DM III. Human apurinic/apyrimidinicendonuclease 1. Antioxid Redox Signal 20: 678707, 2014.

4. McKay BC. Post-transcriptional regulation of DNA damage-responsive gene expression. Antioxid Redox Signal 20: 640654, 2014.

5. Montecucco A and Biamonti G. Pre-mRNA processingfactors meet the DNA damage response. Front Genet 4: 102,2013.

6. Scott TL, Rangaswamy S, Wicker CA, and Izumi T. Repairof oxidative DNA damage and cancer: recent progress inDNA base excision repair. Antioxid Redox Signal 20: 708726, 2014.

7. Sharma V and Misteli T. Non-coding RNAs in DNA damageand repair. FEBS Lett 587: 18321839, 2013.

8. Wan G, Liu Y, Han C, Zhang X, and Lu X. NoncodingRNAs in DNA repair and genome integrity. Antioxid RedoxSignal 20: 655677, 2014.

Address correspondence to:Dr. Chow H. Lee

Chemistry ProgramUniversity of Northern British Columbia

3333 University WayPrince George, BC V2N 4Z9

Canada

E-mail: chow.lee@unbc.ca

Date of first submission to ARS Central, November 6, 2013;date of acceptance, November 18, 2013.

Abbreviations Used

APE1 apurinic/apyrimidinic endonuclease 1BER base excision repairDDRDNA damage responseDKC1 dyskerinncRNA noncoding RNASMUG1 single-strand-selective monofunctional

uracil-DNA glycosylase 1

620 LEE