Abstract
Eukaryotic genomes are replicated with high fidelity to assure the faithful transmission of genetic information from one generation to the next. The accuracy of replication relies heavily on the ability of replicative DNA polymerases to efficiently select correct nucleotides for the polymerization reaction and, using their intrinsic exonuclease activities, to excise mistakenly incorporated nucleotides. Cells also possess a variety of specialized DNA polymerases that, by a process called translesion DNA synthesis (TLS), help overcome replication blocks when unrepaired DNA lesions stall the replication machinery. This review considers the properties of the Y-family (a subset of specialized DNA polymerases) and their roles in modulating spontaneous and genotoxic-induced mutations in mammals. We also review recent insights into the molecular mechanisms that regulate PCNA monoubiquitination and DNA polymerase switching during TLS and discuss the potential of using Y-family DNA polymerases as novel targets for cancer prevention and therapy.
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References
Friedberg EC, Walker GC, Siede W, Wood RD, Schultz RA, Ellenberger T (2005) DNA repair and mutagenesis, 2nd edn. American Society for Microbiology, Washington DC
Friedberg EC (2005) Suffering in silence: the tolerance of DNA damage. Nat Rev Mol Cell Biol 6:943–953
Prakash S, Johnson RE, Prakash L (2005) Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function. Annu Rev Biochem 74:317–353
Ohmori H, Friedberg EC, Fuchs RP, Goodman MF, Hanaoka F, Hinkle D, Kunkel TA, Lawrence CW, Livneh Z, Nohmi T, Prakash L, Prakash S, Todo T, Walker GC, Wang Z, Woodgate R (2001) The Y-family of DNA polymerases. Mol Cell 8:7–8
Yang W, Woodgate R (2007) What a difference a decade makes: insights into translesion DNA synthesis. Proc Natl Acad Sci USA 104:15591–15598
Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, Araki M, Iwai S, Takio K, Hanaoka F (1999) The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature 399:700–704
Johnson RE, Prakash S, Prakash L (1999) Efficient bypass of a thymine–thymine dimer by yeast DNA polymerase, Poleta. Science 283:1001–1004
McDonald JP, Levine AS, Woodgate R (1997) The Saccharomyces cerevisiae RAD30 gene, a homologue of Escherichia coli dinB and umuC, is DNA damage inducible and functions in a novel error-free postreplication repair mechanism. Genetics 147:1557–1568
McDonald JP, Rapic-Otrin V, Epstein JA, Broughton BC, Wang X, Lehmann AR, Wolgemuth DJ, Woodgate R (1999) Novel human and mouse homologs of Saccharomyces cerevisiae DNA polymerase eta. Genomics 60:20–30
Yuasa M, Masutani C, Eki T, Hanaoka F (2000) Genomic structure, chromosomal localization and identification of mutations in the xeroderma pigmentosum variant (XPV) gene. Oncogene 19:4721–4728
Thakur M, Wernick M, Collins C, Limoli CL, Crowley E, Cleaver JE (2001) DNA polymerase eta undergoes alternative splicing, protects against UV sensitivity and apoptosis, and suppresses Mre11-dependent recombination. Genes Chromosomes Cancer 32:222–235
Pabla R, Rozario D, Siede W (2008) Regulation of Saccharomyces cerevisiae DNA polymerase eta transcript and protein. Radiat Environ Biophys 47:157–168
Skoneczna A, McIntyre J, Skoneczny M, Policinska Z, Sledziewska-Gojska E (2007) Polymerase eta is a short-lived, proteasomally degraded protein that is temporarily stabilized following UV irradiation in Saccharomyces cerevisiae. J Mol Biol 366:1074–1086
Liu G, Chen X (2006) DNA polymerase eta, the product of the xeroderma pigmentosum variant gene and a target of p53, modulates the DNA damage checkpoint and p53 activation. Mol Cell Biol 26:1398–1413
Cleaver JE, Bartholomew J, Char D, Crowley E, Feeney L, Limoli CL (2002) Polymerase eta and p53 jointly regulate cell survival, apoptosis and Mre11 recombination during S phase checkpoint arrest after UV irradiation. DNA Repair (Amst) 1:41–57
Cleaver JE, Afzal V, Feeney L, McDowell M, Sadinski W, Volpe JP, Busch DB, Coleman DM, Ziffer DW, Yu Y, Nagasawa H, Little JB (1999) Increased ultraviolet sensitivity and chromosomal instability related to P53 function in the xeroderma pigmentosum variant. Cancer Res 59:1102–1108
Trincao J, Johnson RE, Escalante CR, Prakash S, Prakash L, Aggarwal AK (2001) Structure of the catalytic core of S. cerevisiae DNA polymerase eta: implications for translesion DNA synthesis. Mol Cell 8:417–426
Haracska L, Yu SL, Johnson RE, Prakash L, Prakash S (2000) Efficient and accurate replication in the presence of 7, 8-dihydro-8-oxoguanine by DNA polymerase eta. Nat Genet 25:458–461
Maga G, Villani G, Crespan E, Wimmer U, Ferrari E, Bertocci B, Hubscher U (2007) 8-oxo-guanine bypass by human DNA polymerases in the presence of auxiliary proteins. Nature 447:606–608
Lee DH, Pfeifer GP (2008) Translesion synthesis of 7, 8-dihydro-8-oxo-2′-deoxyguanosine by DNA polymerase eta in vivo. Mutat Res 641:19–26
Busuttil RA, Lin Q, Stambrook PJ, Kucherlapati R, Vijg J (2008) Mutation frequencies and spectra in DNA polymerase eta-deficient mice. Cancer Res 68:2081–2084
Avkin S, Livneh Z (2002) Efficiency, specificity and DNA polymerase-dependence of translesion replication across the oxidative DNA lesion 8-oxoguanine in human cells. Mutat Res 510:81–90
Vaisman A, Masutani C, Hanaoka F, Chaney SG (2000) Efficient translesion replication past oxaliplatin and cisplatin GpG adducts by human DNA polymerase eta. Biochemistry 39:4575–4580
Shachar S, Ziv O, Avkin S, Adar S, Wittschieben J, Reissner T, Chaney S, Friedberg EC, Wang Z, Carell T, Geacintov N, Livneh Z (2009) Two-polymerase mechanisms dictate error-free and error-prone translesion DNA synthesis in mammals. EMBO J 28:383–393
Bassett E, King NM, Bryant MF, Hector S, Pendyala L, Chaney SG, Cordeiro-Stone M (2004) The role of DNA polymerase eta in translesion synthesis past platinum-DNA adducts in human fibroblasts. Cancer Res 64:6469–6475
Chiapperino D, Kroth H, Kramarczuk IH, Sayer JM, Masutani C, Hanaoka F, Jerina DM, Cheh AM (2002) Preferential misincorporation of purine nucleotides by human DNA polymerase eta opposite benzo[a]pyrene 7, 8-diol 9, 10-epoxide deoxyguanosine adducts. J Biol Chem 277:11765–11771
Yang W (2003) Damage repair DNA polymerases Y. Curr Opin Struct Biol 13:23–30
Kannouche P, Broughton BC, Volker M, Hanaoka F, Mullenders LH, Lehmann AR (2001) Domain structure, localization, and function of DNA polymerase eta, defective in xeroderma pigmentosum variant cells. Genes Dev 15:158–172
Bienko M, Green CM, Crosetto N, Rudolf F, Zapart G, Coull B, Kannouche P, Wider G, Peter M, Lehmann AR, Hofmann K, Dikic I (2005) Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science 310:1821–1824
Tissier A, Kannouche P, Reck MP, Lehmann AR, Fuchs RP, Cordonnier A (2004) Co-localization in replication foci and interaction of human Y-family members, DNA polymerase pol eta and REVl protein. DNA Repair (Amst) 3:1503–1514
Ohashi E, Murakumo Y, Kanjo N, Akagi J, Masutani C, Hanaoka F, Ohmori H (2004) Interaction of hREV1 with three human Y-family DNA polymerases. Genes Cells 9:523–531
Akagi JI, Masutani C, Kataoka Y, Kan T, Ohashi E, Mori T, Ohmori H, Hanaoka F (2009) Interaction with DNA polymerase eta is required for nuclear accumulation of REV1 and suppression of spontaneous mutations in human cells. DNA Repair (Amst) (in press)
Ohashi E, Hanafusa T, Kamei K, Song I, Tomida J, Hashimoto H, Vaziri C, Ohmori H (2009) Identification of a novel REV1-interacting motif necessary for DNA polymerase kappa function. Genes Cells 14:101–111
Kosarek JN, Woodruff RV, Rivera-Begeman A, Guo C, D’Souza S, Koonin EV, Walker GC, Friedberg EC (2008) Comparative analysis of in vivo interactions between Rev1 protein and other Y-family DNA polymerases in animals and yeasts. DNA Repair (Amst) 7:439–451
Haracska L, Johnson RE, Unk I, Phillips B, Hurwitz J, Prakash L, Prakash S (2001) Physical and functional interactions of human DNA polymerase eta with PCNA. Mol Cell Biol 21:7199–7206
Acharya N, Yoon JH, Gali H, Unk I, Haracska L, Johnson RE, Hurwitz J, Prakash L, Prakash S (2008) Roles of PCNA-binding and ubiquitin-binding domains in human DNA polymerase eta in translesion DNA synthesis. Proc Natl Acad Sci USA 105:17724–17729
Kannouche PL, Wing J, Lehmann AR (2004) Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol Cell 14:491–500
Plosky BS, Vidal AE, Fernandez de Henestrosa AR, McLenigan MP, McDonald JP, Mead S, Woodgate R (2006) Controlling the subcellular localization of DNA polymerases iota and eta via interactions with ubiquitin. EMBO J 25:2847–2855
Watanabe K, Tateishi S, Kawasuji M, Tsurimoto T, Inoue H, Yamaizumi M (2004) Rad18 guides poleta to replication stalling sites through physical interaction and PCNA monoubiquitination. EMBO J 23:3886–3896
Parker JL, Bielen AB, Dikic I, Ulrich HD (2007) Contributions of ubiquitin- and PCNA-binding domains to the activity of Polymerase eta in Saccharomyces cerevisiae. Nucleic Acids Res 35:881–889
Kannouche PL, Lehmann AR (2004) Ubiquitination of PCNA and the polymerase switch in human cells. Cell Cycle 3:1011–1013
Zhuang Z, Johnson RE, Haracska L, Prakash L, Prakash S, Benkovic SJ (2008) Regulation of polymerase exchange between Poleta and Poldelta by monoubiquitination of PCNA and the movement of DNA polymerase holoenzyme. Proc Natl Acad Sci USA 105:5361–5366
Garg P, Burgers PM (2005) Ubiquitinated proliferating cell nuclear antigen activates translesion DNA polymerases eta and REV1. Proc Natl Acad Sci USA 102:18361–18366
Haracska L, Unk I, Prakash L, Prakash S (2006) Ubiquitylation of yeast proliferating cell nuclear antigen and its implications for translesion DNA synthesis. Proc Natl Acad Sci USA 103:6477–6482
Sabbioneda S, Gourdin AM, Green CM, Zotter A, Giglia-Mari G, Houtsmuller A, Vermeulen W, Lehmann AR (2008) Effect of proliferating cell nuclear antigen ubiquitination and chromatin structure on the dynamic properties of the Y-family DNA polymerases. Mol Biol Cell 19:5193–5202
Acharya N, Yoon JH, Gali H, Unk I, Haracska L, Johnson RE, Hurwitz J, Prakash L, Prakash S (2008) Roles of PCNA-binding and ubiquitin-binding domains in human DNA polymerase {eta} in translesion DNA synthesis. Proc Natl Acad Sci USA 105:17724–17729
Chen YW, Cleaver JE, Hatahet Z, Honkanen RE, Chang JY, Yen Y, Chou KM (2008) Human DNA polymerase eta activity and translocation is regulated by phosphorylation. Proc Natl Acad Sci USA 105:16578–16583
Guo C, Fischhaber PL, Luk-Paszyc MJ, Masuda Y, Zhou J, Kamiya K, Kisker C, Friedberg EC (2003) Mouse Rev1 protein interacts with multiple DNA polymerases involved in translesion DNA synthesis. EMBO J 22:6621–6630
Soria G, Speroni J, Podhajcer OL, Prives C, Gottifredi V (2008) p21 differentially regulates DNA replication and DNA-repair-associated processes after UV irradiation. J Cell Sci 121:3271–3282
Kamath-Loeb AS, Lan L, Nakajima S, Yasui A, Loeb LA (2007) Werner syndrome protein interacts functionally with translesion DNA polymerases. Proc Natl Acad Sci USA 104:10394–10399
Delbos F, De Smet A, Faili A, Aoufouchi S, Weill JC, Reynaud CA (2005) Contribution of DNA polymerase eta to immunoglobulin gene hypermutation in the mouse. J Exp Med 201:1191–1196
Lin Q, Clark AB, McCulloch SD, Yuan T, Bronson RT, Kunkel TA, Kucherlapati R (2006) Increased susceptibility to UV-induced skin carcinogenesis in polymerase eta-deficient mice. Cancer Res 66:87–94
Martomo SA, Yang WW, Wersto RP, Ohkumo T, Kondo Y, Yokoi M, Masutani C, Hanaoka F, Gearhart PJ (2005) Different mutation signatures in DNA polymerase eta- and MSH6-deficient mice suggest separate roles in antibody diversification. Proc Natl Acad Sci USA 102:8656–8661
Friedberg EC, Meira LB (2006) Database of mouse strains carrying targeted mutations in genes affecting biological responses to DNA damage Version 7. DNA Repair (Amst) 5:189–209
Cleaver JE (1972) Xeroderma pigmentosum: variants with normal DNA repair and normal sensitivity to ultraviolet light. J Invest Dermatol 58:124–128
Lehmann AR, Niimi A, Ogi T, Brown S, Sabbioneda S, Wing JF, Kannouche PL, Green CM (2007) Translesion synthesis: Y-family polymerases and the polymerase switch. DNA Repair (Amst) 6:891–899
Wang Y, Woodgate R, McManus TP, Mead S, McCormick JJ, Maher VM (2007) Evidence that in xeroderma pigmentosum variant cells, which lack DNA polymerase eta, DNA polymerase iota causes the very high frequency and unique spectrum of UV-induced mutations. Cancer Res 67:3018–3026
Dumstorf CA, Clark AB, Lin Q, Kissling GE, Yuan T, Kucherlapati R, McGregor WG, Kunkel TA (2006) Participation of mouse DNA polymerase iota in strand-biased mutagenic bypass of UV photoproducts and suppression of skin cancer. Proc Natl Acad Sci USA 103:18083–18088
Tissier A, Frank EG, McDonald JP, Iwai S, Hanaoka F, Woodgate R (2000) Misinsertion and bypass of thymine–thymine dimers by human DNA polymerase iota. EMBO J 19:5259–5266
Zan H, Shima N, Xu Z, Al-Qahtani A, Evinger Iii AJ, Zhong Y, Schimenti JC, Casali P (2005) The translesion DNA polymerase theta plays a dominant role in immunoglobulin gene somatic hypermutation. EMBO J 24:3757–3769
Masuda K, Ouchida R, Takeuchi A, Saito T, Koseki H, Kawamura K, Tagawa M, Tokuhisa T, Azuma T, O-Wang J (2005) DNA polymerase theta contributes to the generation of C/G mutations during somatic hypermutation of Ig genes. Proc Natl Acad Sci USA 102:13986–13991
Zan H, Komori A, Li Z, Cerutti A, Schaffer A, Flajnik MF, Diaz M, Casali P (2001) The translesion DNA polymerase zeta plays a major role in Ig and bcl-6 somatic hypermutation. Immunity 14:643–653
Zeng X, Winter DB, Kasmer C, Kraemer KH, Lehmann AR, Gearhart PJ (2001) DNA polymerase eta is an A–T mutator in somatic hypermutation of immunoglobulin variable genes. Nat Immunol 2:537–541
Faili A, Aoufouchi S, Weller S, Vuillier F, Stary A, Sarasin A, Reynaud CA, Weill JC (2004) DNA polymerase eta is involved in hypermutation occurring during immunoglobulin class switch recombination. J Exp Med 199:265–270
Delbos F, Aoufouchi S, Faili A, Weill JC, Reynaud CA (2007) DNA polymerase eta is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse. J Exp Med 204:17–23
Steele EJ (2004) DNA polymerase-eta as a reverse transcriptase: implications for mechanisms of hypermutation in innate anti-retroviral defences and antibody SHM systems. DNA Repair (Amst) 3:687–692
Kawamoto T, Araki K, Sonoda E, Yamashita YM, Harada K, Kikuchi K, Masutani C, Hanaoka F, Nozaki K, Hashimoto N, Takeda S (2005) Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis. Mol Cell 20:793–799
McIlwraith MJ, Vaisman A, Liu Y, Fanning E, Woodgate R, West SC (2005) Human DNA polymerase eta promotes DNA synthesis from strand invasion intermediates of homologous recombination. Mol Cell 20:783–792
Ishikawa T, Uematsu N, Mizukoshi T, Iwai S, Iwasaki H, Masutani C, Hanaoka F, Ueda R, Ohmori H, Todo T (2001) Mutagenic and nonmutagenic bypass of DNA lesions by Drosophila DNA polymerases dpoleta and dpoliota. J Biol Chem 276:15155–15163
McDonald JP, Tissier A, Frank EG, Iwai S, Hanaoka F, Woodgate R (2001) DNA polymerase iota and related rad30-like enzymes. Philos Trans R Soc Lond B Biol Sci 356:53–60
Tissier A, McDonald JP, Frank EG, Woodgate R (2000) poliota, a remarkably error-prone human DNA polymerase. Genes Dev 14:1642–1650
Vaisman A, Frank EG, McDonald JP, Tissier A, Woodgate R (2002) poliota-dependent lesion bypass in vitro. Mutat Res 510:9–22
Tissier A, Frank EG, McDonald JP, Vaisman A, Fernandez de Henestrosa AR, Boudsocq F, McLenigan MP, Woodgate R (2001) Biochemical characterization of human DNA polymerase iota provides clues to its biological function. Biochem Soc Trans 29:183–187
McDonald JP, Frank EG, Plosky BS, Rogozin IB, Masutani C, Hanaoka F, Woodgate R, Gearhart PJ (2003) 129-derived strains of mice are deficient in DNA polymerase iota and have normal immunoglobulin hypermutation. J Exp Med 198:635–643
Vidal AE, Kannouche P, Podust VN, Yang W, Lehmann AR, Woodgate R (2004) Proliferating cell nuclear antigen-dependent coordination of the biological functions of human DNA polymerase iota. J Biol Chem 279:48360–48368
Frank EG, Tissier A, McDonald JP, Rapic-Otrin V, Zeng X, Gearhart PJ, Woodgate R (2001) Altered nucleotide misinsertion fidelity associated with poliota-dependent replication at the end of a DNA template. EMBO J 20:2914–2922
Wang M, Devereux TR, Vikis HG, McCulloch SD, Holliday W, Anna C, Wang Y, Bebenek K, Kunkel TA, Guan K, You M (2004) Pol iota is a candidate for the mouse pulmonary adenoma resistance 2 locus, a major modifier of chemically induced lung neoplasia. Cancer Res 64:1924–1931
Lee GH, Nishimori H, Sasaki Y, Matsushita H, Kitagawa T, Tokino T (2003) Analysis of lung tumorigenesis in chimeric mice indicates the Pulmonary adenoma resistance 2 (Par2) locus to operate in the tumor-initiation stage in a cell-autonomous manner: detection of polymorphisms in the Poli gene as a candidate for Par2. Oncogene 22:2374–2382
Zhang Y, Yuan F, Wu X, Wang Z (2000) Preferential incorporation of G opposite template T by the low-fidelity human DNA polymerase iota. Mol Cell Biol 20:7099–7108
Johnson RE, Washington MT, Haracska L, Prakash S, Prakash L (2000) Eukaryotic polymerases iota and zeta act sequentially to bypass DNA lesions. Nature 406:1015–1019
Nair DT, Johnson RE, Prakash S, Prakash L, Aggarwal AK (2004) Replication by human DNA polymerase-iota occurs by Hoogsteen base-pairing. Nature 430:377–380
Pence MG, Blans P, Zink CN, Hollis T, Fishbein JC, Perrino FW (2009) Lesion bypass of N2-ethylguanine by human DNA polymerase iota. J Biol Chem 284:1732–1740
Nair DT, Johnson RE, Prakash L, Prakash S, Aggarwal AK (2006) An incoming nucleotide imposes an anti to syn conformational change on the templating purine in the human DNA polymerase-iota active site. Structure 14:749–755
Prakash S, Prakash L (2002) Translesion DNA synthesis in eukaryotes: a one- or two-polymerase affair. Genes Dev 16:1872–1883
Haracska L, Acharya N, Unk I, Johnson RE, Hurwitz J, Prakash L, Prakash S (2005) A single domain in human DNA polymerase iota mediates interaction with PCNA: implications for translesion DNA synthesis. Mol Cell Biol 25:1183–1190
Kannouche P, Fernandez de Henestrosa AR, Coull B, Vidal AE, Gray C, Zicha D, Woodgate R, Lehmann AR (2002) Localization of DNA polymerases eta and iota to the replication machinery is tightly co-ordinated in human cells. EMBO J 21:6246–6256
Friedberg EC, Lehmann AR, Fuchs RP (2005) Trading places: how do DNA polymerases switch during translesion DNA synthesis? Mol Cell 18:499–505
Ohkumo T, Kondo Y, Yokoi M, Tsukamoto T, Yamada A, Sugimoto T, Kanao R, Higashi Y, Kondoh H, Tatematsu M, Masutani C, Hanaoka F (2006) UV-B radiation induces epithelial tumors in mice lacking DNA polymerase eta and mesenchymal tumors in mice deficient for DNA polymerase iota. Mol Cell Biol 26:7696–7706
Yang J, Chen Z, Liu Y, Hickey RJ, Malkas LH (2004) Altered DNA polymerase iota expression in breast cancer cells leads to a reduction in DNA replication fidelity and a higher rate of mutagenesis. Cancer Res 64:5597–5607
Lee GH, Matsushita H (2005) Genetic linkage between Pol iota deficiency and increased susceptibility to lung tumors in mice. Cancer Sci 96:256–259
Faili A, Aoufouchi S, Flatter E, Gueranger Q, Reynaud CA, Weill JC (2002) Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA polymerase iota. Nature 419:944–947
Martomo SA, Yang WW, Vaisman A, Maas A, Yokoi M, Hoeijmakers JH, Hanaoka F, Woodgate R, Gearhart PJ (2006) Normal hypermutation in antibody genes from congenic mice defective for DNA polymerase iota. DNA Repair (Amst) 5:392–398
Shimizu T, Azuma T, Ishiguro M, Kanjo N, Yamada S, Ohmori H (2005) Normal immunoglobulin gene somatic hypermutation in Pol kappa–Pol iota double-deficient mice. Immunol Lett 98:259–264
Vaisman A, Woodgate R (2001) Unique misinsertion specificity of poliota may decrease the mutagenic potential of deaminated cytosines. EMBO J 20:6520–6529
Zhang Y, Yuan F, Wu X, Taylor JS, Wang Z (2001) Response of human DNA polymerase iota to DNA lesions. Nucleic Acids Res 29:928–935
Ito A, Koshikawa N, Mochizuki S, Omura K, Takenaga K (2006) Hypoxia-inducible factor-1 mediates the expression of DNA polymerase iota in human tumor cells. Biochem Biophys Res Commun 351:306–311
Bebenek K, Tissier A, Frank EG, McDonald JP, Prasad R, Wilson SH, Woodgate R, Kunkel TA (2001) 5′-Deoxyribose phosphate lyase activity of human DNA polymerase iota in vitro. Science 291:2156–2159
Prasad R, Bebenek K, Hou E, Shock DD, Beard WA, Woodgate R, Kunkel TA, Wilson SH (2003) Localization of the deoxyribose phosphate lyase active site in human DNA polymerase iota by controlled proteolysis. J Biol Chem 278:29649–29654
Petta TB, Nakajima S, Zlatanou A, Despras E, Couve-Privat S, Ishchenko A, Sarasin A, Yasui A, Kannouche P (2008) Human DNA polymerase iota protects cells against oxidative stress. EMBO J 27:2883–2895
Lawrence CW (2004) Cellular functions of DNA polymerase zeta and Rev1 protein. Adv Protein Chem 69:167–203
Nelson JR, Gibbs PE, Nowicka AM, Hinkle DC, Lawrence CW (2000) Evidence for a second function for Saccharomyces cerevisiae Rev1p. Mol Microbiol 37:549–554
Lawrence CW (2002) Cellular roles of DNA polymerase zeta and Rev1 protein. DNA Repair (Amst) 1:425–435
Lin W, Xin H, Zhang Y, Wu X, Yuan F, Wang Z (1999) The human REV1 gene codes for a DNA template-dependent dCMP transferase. Nucleic Acids Res 27:4468–4475
Masuda Y, Takahashi M, Fukuda S, Sumii M, Kamiya K (2002) Mechanisms of dCMP transferase reactions catalyzed by mouse Rev1 protein. J Biol Chem 277:3040–3046
Masuda Y, Takahashi M, Tsunekuni N, Minami T, Sumii M, Miyagawa K, Kamiya K (2001) Deoxycytidyl transferase activity of the human REV1 protein is closely associated with the conserved polymerase domain. J Biol Chem 276:15051–15058
Murakumo Y, Ogura Y, Ishii H, Numata S, Ichihara M, Croce CM, Fishel R, Takahashi M (2001) Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7. J Biol Chem 276:35644–35651
Waters LS, Walker GC (2006) The critical mutagenic translesion DNA polymerase Rev1 is highly expressed during G(2)/M phase rather than S phase. Proc Natl Acad Sci USA 103:8971–8976
Sabbioneda S, Bortolomai I, Giannattasio M, Plevani P, Muzi-Falconi M (2007) Yeast Rev1 is cell cycle regulated, phosphorylated in response to DNA damage and its binding to chromosomes is dependent upon MEC1. DNA Repair (Amst) 6:121–127
Nair DT, Johnson RE, Prakash L, Prakash S, Aggarwal AK (2005) Rev1 employs a novel mechanism of DNA synthesis using a protein template. Science 309:2219–2222
Masuda Y, Kamiya K (2006) Role of single-stranded DNA in targeting REV1 to primer termini. J Biol Chem 281:24314–24321
Gerlach VL, Aravind L, Gotway G, Schultz RA, Koonin EV, Friedberg EC (1999) Human and mouse homologs of Escherichia coli DinB (DNA polymerase IV), members of the UmuC/DinB superfamily. Proc Natl Acad Sci USA 96:11922–11927
Jansen JG, Tsaalbi-Shtylik A, Langerak P, Calleja F, Meijers CM, Jacobs H, de Wind N (2005) The BRCT domain of mammalian Rev1 is involved in regulating DNA translesion synthesis. Nucleic Acids Res 33:356–365
Huyton T, Bates PA, Zhang X, Sternberg MJ, Freemont PS (2000) The BRCA1 C-terminal domain: structure and function. Mutat Res 460:319–332
Guo C, Sonoda E, Tang TS, Parker JL, Bielen AB, Takeda S, Ulrich HD, Friedberg EC (2006) REV1 protein interacts with PCNA: significance of the REV1 BRCT domain in vitro and in vivo. Mol Cell 23:265–271
Guo C, Tang TS, Bienko M, Parker JL, Bielen AB, Sonoda E, Takeda S, Ulrich HD, Dikic I, Friedberg EC (2006) Ubiquitin-binding motifs in REV1 protein are required for its role in the tolerance of DNA damage. Mol Cell Biol 26:8892–8900
Wood A, Garg P, Burgers PM (2007) A ubiquitin-binding motif in the translesion DNA polymerase Rev1 mediates its essential functional interaction with ubiquitinated proliferating cell nuclear antigen in response to DNA damage. J Biol Chem 282:20256–20263
Ross AL, Simpson LJ, Sale JE (2005) Vertebrate DNA damage tolerance requires the C-terminus but not BRCT or transferase domains of REV1. Nucleic Acids Res 33:1280–1289
D’Souza S, Waters LS, Walker GC (2008) Novel conserved motifs in Rev1 C-terminus are required for mutagenic DNA damage tolerance. DNA Repair (Amst) 7:1455–1470
Masuda Y, Ohmae M, Masuda K, Kamiya K (2003) Structure and enzymatic properties of a stable complex of the human REV1 and REV7 proteins. J Biol Chem 278:12356–12360
Yuasa MS, Masutani C, Hirano A, Cohn MA, Yamaizumi M, Nakatani Y, Hanaoka F (2006) A human DNA polymerase eta complex containing Rad18, Rad6 and Rev1; proteomic analysis and targeting of the complex to the chromatin-bound fraction of cells undergoing replication fork arrest. Genes Cells 11:731–744
Murakumo Y, Mizutani S, Yamaguchi M, Ichihara M, Takahashi M (2006) Analyses of ultraviolet-induced focus formation of hREV1 protein. Genes Cells 11:193–205
Mukhopadhyay S, Clark DR, Watson NB, Zacharias W, McGregor WG (2004) REV1 accumulates in DNA damage-induced nuclear foci in human cells and is implicated in mutagenesis by benzo[a]pyrenediolepoxide. Nucleic Acids Res 32:5820–5826
Niedzwiedz W, Mosedale G, Johnson M, Ong CY, Pace P, Patel KJ (2004) The Fanconi anaemia gene FANCC promotes homologous recombination and error-prone DNA repair. Mol Cell 15:607–620
Mirchandani KD, McCaffrey RM, D’Andrea AD (2008) The Fanconi anemia core complex is required for efficient point mutagenesis and Rev1 foci assembly. DNA Repair (Amst) 7:902–911
Szuts D, Marcus AP, Himoto M, Iwai S, Sale JE (2008) REV1 restrains DNA polymerase {zeta} to ensure frame fidelity during translesion synthesis of UV photoproducts in vivo. Nucleic Acids Res 36:6767–6780
Clark DR, Zacharias W, Panaitescu L, McGregor WG (2003) Ribozyme-mediated REV1 inhibition reduces the frequency of UV-induced mutations in the human HPRT gene. Nucleic Acids Res 31:4981–4988
Gibbs PE, Wang XD, Li Z, McManus TP, McGregor WG, Lawrence CW, Maher VM (2000) The function of the human homolog of Saccharomyces cerevisiae REV1 is required for mutagenesis induced by UV light. Proc Natl Acad Sci USA 97:4186–4191
Poltoratsky V, Horton JK, Prasad R, Wilson SH (2005) REV1 mediated mutagenesis in base excision repair deficient mouse fibroblast. DNA Repair (Amst) 4:1182–1188
Simpson LJ, Sale JE (2003) Rev1 is essential for DNA damage tolerance and non-templated immunoglobulin gene mutation in a vertebrate cell line. EMBO J 22:1654–1664
Jansen JG, Langerak P, Tsaalbi-Shtylik A, van den Berk P, Jacobs H, de Wind N (2006) Strand-biased defect in C/G transversions in hypermutating immunoglobulin genes in Rev1-deficient mice. J Exp Med 203:319–323
Okada T, Sonoda E, Yoshimura M, Kawano Y, Saya H, Kohzaki M, Takeda S (2005) Multiple roles of vertebrate REV genes in DNA repair and recombination. Mol Cell Biol 25:6103–6111
Sakiyama T, Kohno T, Mimaki S, Ohta T, Yanagitani N, Sobue T, Kunitoh H, Saito R, Shimizu K, Hirama C, Kimura J, Maeno G, Hirose H, Eguchi T, Saito D, Ohki M, Yokota J (2005) Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk. Int J Cancer 114:730–737
He X, Ye F, Zhang J, Cheng Q, Shen J, Chen H (2008) REV1 genetic variants associated with the risk of cervical carcinoma. Eur J Epidemiol 23:403–409
Uljon SN, Johnson RE, Edwards TA, Prakash S, Prakash L, Aggarwal AK (2004) Crystal structure of the catalytic core of human DNA polymerase kappa. Structure (Camb) 12:1395–1404
Jarosz DF, Godoy VG, Walker GC (2007) Proficient and accurate bypass of persistent DNA lesions by DinB DNA polymerases. Cell Cycle 6:817–822
Choi JY, Angel KC, Guengerich FP (2006) Translesion synthesis across bulky N2-alkyl guanine DNA adducts by human DNA polymerase kappa. J Biol Chem 281:21062–21072
Ogi T, Kato T Jr, Kato T, Ohmori H (1999) Mutation enhancement by DINB1, a mammalian homologue of the Escherichia coli mutagenesis protein dinB. Genes Cells 4:607–618
Velasco-Miguel S, Richardson JA, Gerlach VL, Lai WC, Gao T, Russell LD, Hladik CL, White CL, Friedberg EC (2003) Constitutive and regulated expression of the mouse Dinb (Polkappa) gene encoding DNA polymerase kappa. DNA Repair (Amst) 2:91–106
Guo C, Gao T, Confer N, Velasco-Miguel S, Friedberg EC (2005) Multiple PolK (POLK) transcripts in mammalian testis. DNA Repair (Amst) 4:397–402
Ogi T, Mimura J, Hikida M, Fujimoto H, Fujii-Kuriyama Y, Ohmori H (2001) Expression of human and mouse genes encoding polkappa: testis-specific developmental regulation and AhR-dependent inducible transcription. Genes Cells 6:943–953
Lemee F, Bavoux C, Pillaire MJ, Bieth A, Machado CR, Pena SD, Guimbaud R, Selves J, Hoffmann JS, Cazaux C (2007) Characterization of promoter regulatory elements involved in downexpression of the DNA polymerase kappa in colorectal cancer. Oncogene 26:3387–3394
Guo C, Tang TS, Bienko M, Dikic I, Friedberg EC (2008) Requirements for the interaction of mouse Polkappa with ubiquitin and its biological significance. J Biol Chem 283:4658–4664
Ohashi E, Ogi T, Kusumoto R, Iwai S, Masutani C, Hanaoka F, Ohmori H (2000) Error-prone bypass of certain DNA lesions by the human DNA polymerase kappa. Genes Dev 14:1589–1594
Gerlach VL, Feaver WJ, Fischhaber PL, Friedberg EC (2001) Purification and characterization of pol kappa, a DNA polymerase encoded by the human DINB1 gene. J Biol Chem 276:92–98
Rechkoblit O, Zhang Y, Guo D, Wang Z, Amin S, Krzeminsky J, Louneva N, Geacintov NE (2002) trans-Lesion synthesis past bulky benzo[a]pyrene diol epoxide N2-dG and N6-dA lesions catalyzed by DNA bypass polymerases. J Biol Chem 277:30488–30494
Zhang Y, Yuan F, Wu X, Wang M, Rechkoblit O, Taylor JS, Geacintov NE, Wang Z (2000) Error-free and error-prone lesion bypass by human DNA polymerase kappa in vitro. Nucleic Acids Res 28:4138–4146
Suzuki N, Itoh S, Poon K, Masutani C, Hanaoka F, Ohmori H, Yoshizawa I, Shibutani S (2004) Translesion synthesis past estrogen-derived DNA adducts by human DNA polymerases eta and kappa. Biochemistry 43:6304–6311
Fischhaber PL, Gerlach VL, Feaver WJ, Hatahet Z, Wallace SS, Friedberg EC (2002) Human DNA polymerase kappa bypasses and extends beyond thymine glycols during translesion synthesis in vitro, preferentially incorporating correct nucleotides. J Biol Chem 277:37604–37611
Haracska L, Unk I, Johnson RE, Phillips BB, Hurwitz J, Prakash L, Prakash S (2002) Stimulation of DNA synthesis activity of human DNA polymerase kappa by PCNA. Mol Cell Biol 22:784–791
Ogi T, Lehmann AR (2006) The Y-family DNA polymerase kappa (pol kappa) functions in mammalian nucleotide-excision repair. Nat Cell Biol 8:640–642
Lone S, Townson SA, Uljon SN, Johnson RE, Brahma A, Nair DT, Prakash S, Prakash L, Aggarwal AK (2007) Human DNA polymerase kappa encircles DNA: implications for mismatch extension and lesion bypass. Mol Cell 25:601–614
Uljon SN, Johnson RE, Edwards TA, Prakash S, Prakash L, Aggarwal AK (2004) Crystal structure of the catalytic core of human DNA polymerase kappa. Structure 12:1395–1404
Bi X, Barkley LR, Slater DM, Tateishi S, Yamaizumi M, Ohmori H, Vaziri C (2006) Rad18 regulates DNA polymerase kappa and is required for recovery from S-phase checkpoint-mediated arrest. Mol Cell Biol 26:3527–3540
Ogi T, Kannouche P, Lehmann AR (2005) Localisation of human Y-family DNA polymerase kappa: relationship to PCNA foci. J Cell Sci 118:129–136
Bergoglio V, Bavoux C, Verbiest V, Hoffmann JS, Cazaux C (2002) Localisation of human DNA polymerase kappa to replication foci. J Cell Sci 115:4413–4418
Bi X, Slater DM, Ohmori H, Vaziri C (2005) DNA polymerase kappa is specifically required for recovery from the benzo[a]pyrene-dihydrodiol epoxide (BPDE)-induced S-phase checkpoint. J Biol Chem 280:22343–22355
Schenten D, Gerlach VL, Guo C, Velasco-Miguel S, Hladik CL, White CL, Friedberg EC, Rajewsky K, Esposito G (2002) DNA polymerase kappa deficiency does not affect somatic hypermutation in mice. Eur J Immunol 32:3152–3160
Ogi T, Shinkai Y, Tanaka K, Ohmori H (2002) Polkappa protects mammalian cells against the lethal and mutagenic effects of benzo[a]pyrene. Proc Natl Acad Sci USA 99:15548–15553
Burr KL, Velasco-Miguel S, Duvvuri VS, McDaniel LD, Friedberg EC, Dubrova YE (2006) Elevated mutation rates in the germline of Polkappa mutant male mice. DNA Repair (Amst) 5:860–862
Avkin S, Goldsmith M, Velasco-Miguel S, Geacintov N, Friedberg EC, Livneh Z (2004) Quantitative analysis of translesion DNA synthesis across a benzo[a]pyrene-guanine adduct in mammalian cells: the role of DNA polymerase kappa. J Biol Chem 279:53298–53305
Takenaka K, Ogi T, Okada T, Sonoda E, Guo C, Friedberg EC, Takeda S (2006) Involvement of vertebrate Polkappa in translesion DNA synthesis across DNA monoalkylation damage. J Biol Chem 281:2000–2004
Bavoux C, Leopoldino AM, Bergoglio V, O-Wang J, Ogi T, Bieth A, Judde JG, Pena SD, Poupon MF, Helleday T, Tagawa M, Machado C, Hoffmann JS, Cazaux C (2005) Up-regulation of the error-prone DNA polymerase {kappa} promotes pleiotropic genetic alterations and tumorigenesis. Cancer Res 65:325–330
O-Wang J, Kawamura K, Tada Y, Ohmori H, Kimura H, Sakiyama S, Tagawa M (2001) DNA polymerase kappa, implicated in spontaneous and DNA damage-induced mutagenesis, is overexpressed in lung cancer. Cancer Res 61:5366–5369
Bavoux C, Hoffmann JS, Cazaux C (2005) Adaptation to DNA damage and stimulation of genetic instability: the double-edged sword mammalian DNA polymerase kappa. Biochimie 87:637–646
Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S (2002) RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419:135–141
Stelter P, Ulrich HD (2003) Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 425:188–191
Niimi A, Brown S, Sabbioneda S, Kannouche PL, Scott A, Yasui A, Green CM, Lehmann AR (2008) Regulation of proliferating cell nuclear antigen ubiquitination in mammalian cells. Proc Natl Acad Sci USA 105:16125–16130
Davies AA, Huttner D, Daigaku Y, Chen S, Ulrich HD (2008) Activation of ubiquitin-dependent DNA damage bypass is mediated by replication protein a. Mol Cell 29:625–636
Chang DJ, Lupardus PJ, Cimprich KA (2006) Monoubiquitination of proliferating cell nuclear antigen induced by stalled replication requires uncoupling of DNA polymerase and mini-chromosome maintenance helicase activities. J Biol Chem 281:32081–32088
Nakajima S, Lan L, Kanno S, Usami N, Kobayashi K, Mori M, Shiomi T, Yasui A (2006) Replication-dependent and -independent responses of RAD18 to DNA damage in human cells. J Biol Chem 281:34687–34695
Soria G, Podhajcer O, Prives C, Gottifredi V (2006) P21Cip1/WAF1 downregulation is required for efficient PCNA ubiquitination after UV irradiation. Oncogene 25:2829–2838
Gohler T, Munoz IM, Rouse J, Blow JJ (2008) PTIP/Swift is required for efficient PCNA ubiquitination in response to DNA damage. DNA Repair (Amst) 7:775–787
Yang XH, Shiotani B, Classon M, Zou L (2008) Chk1 and Claspin potentiate PCNA ubiquitination. Genes Dev 22:1147–1152
Huang TT, Nijman SM, Mirchandani KD, Galardy PJ, Cohn MA, Haas W, Gygi SP, Ploegh HL, Bernards R, D’Andrea AD (2006) Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol 8:339–347
Lehmann AR, Fuchs RP (2006) Gaps and forks in DNA replication: rediscovering old models. DNA Repair (Amst) 5:1495–1498
Lopes M, Foiani M, Sogo JM (2006) Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. Mol Cell 21:15–27
Langerak P, Nygren AO, Krijger PH, van den Berk PC, Jacobs H (2007) A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification. J Exp Med 204:1989–1998
Roa S, Avdievich E, Peled JU, Maccarthy T, Werling U, Kuang FL, Kan R, Zhao C, Bergman A, Cohen PE, Edelmann W, Scharff MD (2008) Ubiquitylated PCNA plays a role in somatic hypermutation and class-switch recombination and is required for meiotic progression. Proc Natl Acad Sci USA 105:16248–16253
Fu Y, Zhu Y, Zhang K, Yeung M, Durocher D, Xiao W (2008) Rad6-Rad18 mediates a eukaryotic SOS response by ubiquitinating the 9-1-1 checkpoint clamp. Cell 133:601–611
Tomida J, Masuda Y, Hiroaki H, Ishikawa T, Song I, Tsurimoto T, Tateishi S, Shiomi T, Kamei Y, Kim J, Kamiya K, Vaziri C, Ohmori H, Todo T (2008) DNA damage-induced ubiquitylation of RFC2 subunit of replication factor C complex. J Biol Chem 283:9071–9079
Edmunds CE, Simpson LJ, Sale JE (2008) PCNA ubiquitination and REV1 define temporally distinct mechanisms for controlling translesion synthesis in the avian cell line DT40. Mol Cell 30:519–529
McCulloch SD, Kokoska RJ, Kunkel TA (2004) Efficiency, fidelity and enzymatic switching during translesion DNA synthesis. Cell Cycle 3:580–583
McCulloch SD, Kokoska RJ, Masutani C, Iwai S, Hanaoka F, Kunkel TA (2004) Preferential cis–syn thymine dimer bypass by DNA polymerase eta occurs with biased fidelity. Nature 428:97–100
Masutani C, Araki M, Yamada A, Kusumoto R, Nogimori T, Maekawa T, Iwai S, Hanaoka F (1999) Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity. EMBO J 18:3491–3501
Ling H, Boudsocq F, Woodgate R, Yang W (2001) Crystal structure of a Y-family DNA polymerase in action: a mechanism for error-prone and lesion-bypass replication. Cell 107:91–102
Rattray AJ, Strathern JN (2003) Error-prone DNA polymerases: when making a mistake is the only way to get ahead. Annu Rev Genet 37:31–66
Kim SH, Michael WM (2008) Regulated proteolysis of DNA polymerase eta during the DNA-damage response in C. elegans. Mol Cell 32:757–766
Bielas JH, Loeb KR, Rubin BP, True LD, Loeb LA (2006) Human cancers express a mutator phenotype. Proc Natl Acad Sci USA 103:18238–18242
Watson NB, Mukhopadhyay S, McGregor WG (2006) Translesion DNA replication proteins as molecular targets for cancer prevention. Cancer Lett 241:13–22
Li Z, Zhang H, McManus TP, McCormick JJ, Lawrence CW, Maher VM (2002) hREV3 is essential for error-prone translesion synthesis past UV or benzo[a]pyrene diol epoxide-induced DNA lesions in human fibroblasts. Mutat Res 510:71–80
Takezawa J, Ishimi Y, Yamada K (2008) Proteasome inhibitors remarkably prevent translesion replication in cancer cells but not normal cells. Cancer Sci 99:863–871
Dantuma NP, Groothuis TA, Salomons FA, Neefjes J (2006) A dynamic ubiquitin equilibrium couples proteasomal activity to chromatin remodeling. J Cell Biol 173:19–26
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This work was supported by grant ES11344 (NIEHS) (ECF).
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Guo, C., Kosarek-Stancel, J.N., Tang, TS. et al. Y-family DNA polymerases in mammalian cells. Cell. Mol. Life Sci. 66, 2363–2381 (2009). https://doi.org/10.1007/s00018-009-0024-4
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DOI: https://doi.org/10.1007/s00018-009-0024-4