ANTIOXIDANTS & REDOX SIGNALING Volume 12, Number 11, 2010 C OMPREHENSIVE INVITED REVIEW © Mary Ann Liebert, Inc. DOI: 10.1089/ ars.2009.2698 Redox Regulation of DNA Repair: Implications for Human Health and Cancer Therapeutic Development 2 2 Meihua Luo~ Hongzhen He, Mark R. Ke l ley ~ -3 and Millie M. Georgiadis .4 Abstract Red.ox reactions are known to regulate many important cellular processes. In this revievv, v.re focus on the role of redox regulation in DNA repair both in direct regulation of specific DNA repair proteins as well as indirect transcriptional regulation. A key player in the redox regulation of DNA repair is the base excision repair enzyme apurinic/apyrimidinic endonuclease 1 (APEl) in its role as a redox factor. APEl is reduced by the general redox factor thioredoxin, and in turn reduces several important transcription factors that regulate expression of DNA repair proteins. Finally, we consider the potential for chemotherapeutic development through the modulation of APEl's redox activity and its impact on DNA repair. Antioxid. Redox Signal. 12, 1247-1269. l. Introduction 1248 II. DNA-Repair Pathways 1248 A. Mammalian d irect repair: 0 6-alkylguanine-DNA methyltransferase or 0 6-methylguanine-DNA methyltransferase 1249 B. Base-excision repair 1249 C. Nucleotide-excision repair 1249 D. Mismatch repair 1250 E. Nonhomologous DNA end-joining and homologous recombiJ.1ation 1250 ITT. General Redox Systems 1251 A. The thioredoxin system 1251 B. The glutaredoxin/glutathione system 1252 C. l~oles of general redox systems 1252 N. The Redox Activity of APEl 1252 A. Evolution of the redox function of APEl 1252 B. Comparison of APEl with other redox factors 1254 C. Mechanism of redox regulation by APE1 1255 V. Transcription Factors Regulated by the Redox Activity of APEl 1255 A. p53 1256 B. AP-1 1257 C. HIF-la and hypoxia 1258 VT. The Multifunctional APEl and Redox Control 1259 VIL Modulating APEl Activities as a Cancer Therapeutic Approach 1260 A. APEl redox inhibitors 1260 1. E3330 1260 2. Other redox iJ.1hibitors 1261 B. APEl repair iJ.1hibitors 1261 Reviewing Editors: Margherita Bignami, Diego Bonatto, Dindial Ramotar, Young R. Seo, and Silvia Tomaletti 1Department of Pediatrics (Section of HematoloSj,'./ Oncology), Herman B. Wells Center for Pediatric Research, Indiana University; 2 Department of Biochentistry and Molecular Biology, Department of Pharmacology and Toxicology, Indiana U1tiversity School of Medicine; and 4 Department of Chemistry and Chemical Biology, Indiana University-Purdue University at Indianapolis, Indianapolis, lndiana. 1247 1248 LUO ET AL. VIII. Chemoprevention, Redox Modulation, and DNA Repair 1261 A. Dietary antioxidants 1261 1. Ellagic acid 1261 2. Selenium 1261 3. Oltipraz 1262 B. Direct regulation of DNA repair by altered redox status of the cell 1262 IX. Concluding l~emarks 1262 I. Introduction overvievv of general redox systems as well as an in-depth discussion of the redox activity of APEl. Finally, in consider­ LTHOUGH THE IMPORTANCE of DNA-repair pathways in ing the impact of redox regulation of DNA repair to human A protecting the genome from damage caused by endog­ health, we discuss the modulation of the redox activity of enous and exogenous DNA-damaging agents (40, 44, 60) has APEl by small molecules and the potential for chemothera­ long been recognized, the role of redox regulation in these peutic development targeting redox regulation of DNA repair. pathways is a relatively recent discovery. In writing this re­ vie'~', vve attempted to guide the reader through general as II. DNA-Repair Pathways well as specific aspects of DNA repair and redox regulation, focusing ultimately on the connection beh-veen the h-vo. We The genome of eukaryotic cells is constantly under attack begin vvith an overview of DNA-repair pathways leading to a from both endogenous and exogenous DNA-damaging more in-depth discussion of one specific DNA-repair path­ agents. DNA damage resulting from endogenous agents in­ way, the base excision repair (BER) pathway. We focus on the cludes oxidation by reactive oxygen species (ROS) generated BER pathway, which is responsible for the repair of DNA from normal 1netabolic processes, alkylation by agents such as damage caused by oxidation, alkylation, and ionizing radia­ 5-adenosylmethionine, adduct fonnation resulting from at­ tion, and specifically on apurinic/apyrimidinic endonuclease 1 tack by reactive carbonyl species fonned during lipid perox­ (APEl ), the only DNA-repair protein currently known to serve idation, hydrolytic depurination leading to the formation of a dual role as a repair enzyme and a redox factor. In its role as a abasic sites, or deamination of bases, primarily cytidine, and redox factor, APEl modifies downstream trai1scription factors to a lesser extent, adenine (44). Exogenous agents include such as AP-1, NF-KB, CREB, p53, and others, and thereby in­ envirorunental insults (chemicals, carcinogens, UV light), directly alters the activity of other DNA-repair pathways. To che1notherapeutic agents, and radiation dan1age (40, 60). put the redox activity of APEl in perspective, we provide an Failure to repair DNA damage in both postmitotic and mitotic Direct Base Mismatch Nucleotide Non-homologous Homologous Repair Excision Excision End Joining Recombination (HR) (NHEJ) ! MSH2/6 TCR GGR Glycosylase ~ MSH2/3 ! ! RNA Polll, DDB-XPE, Ku70,Ku80 APE1 CSA, CSB, XPC, XPAB2 HR2313 I Long Short MLH1-PMS2 Patch Patch MLH1 -PMS1 DNA-PK RPA, XPA, XPC­ TFllH, XPB, XPC, XPD, XPG, XPF- ERCC1 MRN, Rad51, Rad52, Rad54, BRCA1, BRCA2, PCNA, PolS/&, ! Ligase I EX01, RFC, PCNA, RPA, RFC, PCNA, DNA Pol ~1. XRCC4, NA PolS, Ligase PolS/&, Ligase I Ligase 4, Artemis FIG. 1. Schematic overview of DNA-repair pathway. Several DNA-repair pathways are involved in maintaining cell genomic stability; these include direct repair (DR), base-excision repair (BER), nucleotide-excision repair (NER), mismatch repair (MMI{), homologous recombination (HR), and nonhomologous end joining (NHEJ). More than 150 proteins are involved. Only selected genes of each path\·vay ai·e shown here. [Adapted from Fishel et al. (57).) 1249 REDOX REGULATION OF DNA REPAIR cells can result in apoptosis or accumulation of mutations and B. Base-excision repair even cell-cycle arrest (58, 106). For example, the DN~-dam~ge BER is responsible for the repair of DNA damage arising response in 1nitotic cells results in cell-eye!~ ar_rest mvolvmg fro1n alkylation, d eamination, or oxidation of bases (8, 40, 50). the major cell-cycle machinery. Tn postm1totic cells, DNA Alkylation of bases arises from exposi.rre to either endogenous d amage may result in cell-cycle activation and subsequent agents such as S-adenosylmethionine or exogen~us agents, arrest, leading to deleterious events in this cell population as including environmental and chemotherapeutic agents, well (110, 160). However, we have evolved a series of DNA­ w hereas deamination of cytidines and adenines occurs spon­ repair pathways to correct the damage, incl_uding ~~ect repa~ taneously. Oxidative damage can result from ROS generated (DR), base-excision repair (BER), nucleot1de-exas1on_ re~arr by normal cellular processes, in addition to envirorunental or (NER), mismatch repair (MMR), homologous recomb1n~ti on chemotherapeutic agents. BER is initiated by the removal of (HR), and nonhomologous end joining (NHEJ) (85, 86) (Fig.~) . the damaged base through enzymes called DNA glycosylases, The number of DNA-repair proteins and factors involved 111 which specifically recognize several different types of base the cellular response to DNA damage keeps growing as damage. Glycosylases are of two types, monofunctional and m ore and more information is obtained, not only on the DNA bifunctionaL Monofunctional glycosylases (e.g., N-methyl repair enzymes involved in each path,.vay, but also on the purine DNA glycosylase (MPG or AAG)] excise the d~a~ed regulatory networks that are induced by persis ~ence o_f DNA base to generate an apurinic/ apyrimidinic (AP) or abas1c site, darnage in the cell (182). Distinct DNA damage IS reparred by which is acted on by the multifunctional AP endonuclease, the different pathways and mechanisms. Overlap and inte_r­ APEl. Bi functional glycosylases such as human 8-oxoguanine action between the various pathways and some overlap In ONA glycosylase (hOGGl), human endonuclease VIII- like 6 mechanisn1s occur. For example, 0 -n1ethylguanine can DNA glycosylase (NEILl-3), and E. coli endonucl~ase III 6 be removed directly by 0 -m ethylguanine-DNA methyl­ (NTH) glycosylase have an additional A!' lyase function (~6, transferase (MGMT or AGl) in DR, but if this pathway is not 43) that excises the damaged base and rucks the phosphod1e­ successful, the 0 6mG mispairs and is recognized by the MMR ster backbone 3' to the AP site. The resulting AP site is pro­ pathway (59). Similarly, oxidative DNA dam~ge is ~epaired cessed by APE1, which hydrolyzes the phosphodiester mainly by BER, but som e repair by NER also lS possible (53). backbone immediately 5' to the AP site, creating 3' OH and 5' Single-sh·and DNA breaks (SSBs) unrepaired by BER lead to deoxyribose phosphate (5' dRP) termini. At this stage, repair d ouble-strand breaks (DSBs), which may be repaired by HR, can proceed by two pathways: the short-patch B El~ (SP-BEl~) and HR can also repair DNA DSBs that NHEJ pathways fa il to pathway and the long-patch BER (LP-BER)_ p~th.way. APEl is process (49). Interaction of different DNA-repair pathways responsible for 95°/o of the endonuclease act1v1ty 1n the cell and and mechanisms provides the most efficient defense for the is a critical part of both the short-patch and the long-patch BER cell genome, whereas reduced repair capacity ca:' lead . to pathway (45, 46). SP-BER repairs normal AP sites. DNA genomic instability. A number of diseases are as~oc1a ted with polymerase f3 (pol /3) removes the 5' dRP moiety by its dRPase defects in DNA repair, including xeroderma p1gmentosum , activity and u ses the 3' OH terminus to insert the correct b~s~ .