Mutagenesis is a hallmark and enabling characteristic of cancer cells. The E3 ubiquitin ligase RAD18 and its downstream effectors, the 'Y-family' Trans-Lesion Synthesis (TLS) DNA polymerases, confer DNA damage tolerance at the expense of DNA replication fidelity. Thus, RAD18 and TLS polymerases are attractive candidate mediators of mutagenesis and carcinogenesis. The skin cancer-propensity disorder xeroderma pigmentosum-variant (XPV) is caused by defects in the Y-family DNA polymerase Pol eta (Polη). However it is unknown whether TLS dysfunction contributes more generally to other human cancers. Recent analyses of cancer genomes suggest that TLS polymerases generate many of the mutational signatures present in diverse cancers. Moreover biochemical studies suggest that the TLS pathway is often reprogrammed in cancer cells and that TLS facilitates tolerance of oncogene-induced DNA damage. Here we review recent evidence supporting widespread participation of RAD18 and the Y-family DNA polymerases in the different phases of multi-step carcinogenesis.

b Division of Cell Maintenance Institute of Molecular Embryology and Genetics Kumamoto University Kumamoto Japan

c Life Science Research Center University of Ostrava Ostrava Czech Republic

Department of Pathology and Laboratory Medicine University of North Carolina at Chapel Hill Chapel Hill NC USA

National Center for Biotechnology Information National Library of Medicine National Institutes of Health Bethesda MD USA

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Masutani C, Kusumoto R, Yamada A, et al. . The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature. 1999;399:700–704. doi:10.1038/21447. PMID:10385124 PubMed DOI

Rogozin IB, Goncearenco A, Lada AG, et al. . DNA polymerase eta mutational signatures are found in a variety of different types of cancer. Cell Cycle . 2018;17(3):348–355. doi:10.1080/15384101.2017.1404208. PubMed DOI PMC

Gao Y, Mutter-Rottmayer E, Greenwalt AM, et al. . A neomorphic cancer cell-specific role of MAGE-A4 in trans-lesion synthesis. Nat Commun. 2016;7:12105. doi:10.1038/ncomms12105. PMID:27377895 PubMed DOI PMC

Gao Y, Tateishi S, Vaziri C. Pathological trans-lesion synthesis in cancer. Cell Cycle . 2016;15(22):3005–3006. doi:10.1080/15384101.2016.1214045. PubMed DOI PMC

Yang Y, Gao Y, Mutter-Rottmayer L, et al. . DNA repair factor RAD18 and DNA polymerase Polkappa confer tolerance of oncogenic DNA replication stress. J Cell Biol. 2017;216(10):3097. doi:10.1083/jcb.201702006. PubMed DOI PMC

Albertella MR, Green CM, Lehmann AR, et al. . A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. Cancer Res. 2005;65:9799–9806. doi:10.1158/0008-5472.CAN-05-1095. PMID:16267001 PubMed DOI

Zhao Y, Biertumpfel C, Gregory MT, et al. . Structural basis of human DNA polymerase eta-mediated chemoresistance to cisplatin. Proc Natl Acad Sci USA. 2012;109:7269–7274. doi:10.1073/pnas.1202681109. PMID:22529383 PubMed DOI PMC

Masutani C, Araki M, Yamada A, et al. . Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity. Embo J. 1999;18:3491–3501. doi:10.1093/emboj/18.12.3491. PMID:10369688 PubMed DOI PMC

Ziv O, Geacintov N, Nakajima S, et al. . DNA polymerase zeta cooperates with polymerases kappa and iota in translesion DNA synthesis across pyrimidine photodimers in cells from XPV patients. Proc Natl Acad Sci USA. 2009;106:11552–11557. doi:10.1073/pnas.0812548106. PMID:19564618 PubMed DOI PMC

Shachar S, Ziv O, Avkin S, et al. . Two-polymerase mechanisms dictate error-free and error-prone translesion DNA synthesis in mammals. EMBO J. 2009;28:383–393. doi:10.1038/emboj.2008.281. PMID:19153606 PubMed DOI PMC

Ohmori H, Ohashi E, Ogi T. Mammalian Pol kappa: regulation of its expression and lesion substrates. Adv Protein Chem. 2004;69:265–278. doi:10.1016/S0065-3233(04)69009-7. PMID:15588846 PubMed DOI

Ulrich HD, Jentsch S. Two RING finger proteins mediate cooperation between ubiquitin-conjugating enzymes in DNA repair. EMBO J. 2000;19:3388–3397. doi:10.1093/emboj/19.13.3388. PMID:10880451 PubMed DOI PMC

Kannouche PL, Wing J, Lehmann AR. Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol Cell. 2004;14:491–500. doi:10.1016/S1097-2765(04)00259-X. PMID:15149598 PubMed DOI

Davies AA, Huttner D, Daigaku Y, et al. . Activation of ubiquitin-dependent DNA damage bypass is mediated by replication protein a. Mol Cell. 2008;29:625–636. doi:10.1016/j.molcel.2007.12.016. PMID:18342608 PubMed DOI PMC

Zou L, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003;300:1542–1548. doi:10.1126/science.1083430. PMID:12791985 PubMed DOI

Yang Y, Durando M, Smith-Roe SL, et al. . Cell cycle stage-specific roles of Rad18 in tolerance and repair of oxidative DNA damage. Nucleic Acids Res. 2013;41(4):2296–2312. doi:10.1093/nar/gks1325. PubMed DOI PMC

Zlatanou A, Despras E, Braz-Petta T, et al. . The hMsh2-hMsh6 complex acts in concert with monoubiquitinated PCNA and Pol eta in response to oxidative DNA damage in human cells. Mol Cell. 2011;43:649–662. doi:10.1016/j.molcel.2011.06.023. PMID:21855803 PubMed DOI

Ogi T, Limsirichaikul S, Overmeer RM, et al. . Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells. Mol Cell. 2010;37:714–727. doi:10.1016/j.molcel.2010.02.009. PMID:20227374 PubMed DOI

Bienko M, Green CM, Crosetto N, et al. . Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science. 2005;310:1821–1824. doi:10.1126/science.1120615. PMID:16357261 PubMed DOI

Watanabe K, Tateishi S, Kawasuji M, et al. . Rad18 guides poleta to replication stalling sites through physical interaction and PCNA monoubiquitination. Embo J. 2004;23:3886–3896. doi:10.1038/sj.emboj.7600383. PMID:15359278 PubMed DOI PMC

Durando M, Tateishi S, Vaziri C. A non-catalytic role of DNA polymerase eta in recruiting Rad18 and promoting PCNA monoubiquitination at stalled replication forks. Nucleic Acids Res. 2013;41(5):3079–3093. doi:10.1093/nar/gkt016. PubMed DOI PMC

Rogozin IB, Pavlov YI, Goncearenco A, et al. . Mutational signatures and mutable motifs in cancer genomes. Brief Bioinform. 2017;1–17. doi:10.1093/bib/bbx049. PMID:28498882 PubMed DOI PMC

Alexandrov LB, Stratton MR. Mutational signatures: the patterns of somatic mutations hidden in cancer genomes. Curr Opin Gene Dev. 2014;24:52–60. doi:10.1016/j.gde.2013.11.014. PubMed DOI PMC

Temiz NA, Donohue DE, Bacolla A, et al. . The somatic autosomal mutation matrix in cancer genomes. Hum Genet. 2015;134:851–864. doi:10.1007/s00439-015-1566-1. PMID:26001532 PubMed DOI PMC

Goncearenco A, Rager SL, Li M, et al. . Exploring background mutational processes to decipher cancer genetic heterogeneity. Nucleic Acids Res. 2017;45(W1):W514–W522. doi:10.1093/nar/gkx367. PMID:28472504 PubMed DOI PMC

Alexandrov LB, Nik-Zainal S, Wedge DC, et al. . Signatures of mutational processes in human cancer. Nature. 2013;500:415–21. doi:10.1038/nature12477. PMID:23945592 PubMed DOI PMC

Roberts SA, Sterling J, Thompson C, et al. . Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol Cell. 2012;46:424–435. doi:10.1016/j.molcel.2012.03.030. PMID:22607975 PubMed DOI PMC

Chan K, Gordenin DA. Clusters of multiple mutations: incidence and molecular mechanisms. Annu Rev Genet. 2015;49:243–67. doi:10.1146/annurev-genet-112414-054714. PMID:26631512 PubMed DOI PMC

Tsuji Y, Watanabe K, Araki K, et al. . Recognition of forked and single-stranded DNA structures by human RAD18 complexed with RAD6B protein triggers its recruitment to stalled replication forks. Genes Cells. 2008;13:343–354. doi:10.1111/j.1365-2443.2008.01176.x. PMID:18363965 PubMed DOI

Buisson R, Lawrence MS, Benes CH, et al. . APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition. Cancer Res. 2017;77:4567–4578. doi:10.1158/0008-5472.CAN-16-3389. PMID:28698210 PubMed DOI PMC

Mayorov VI, Rogozin IB, Adkison LR, et al. . DNA polymerase eta contributes to strand bias of mutations of A versus T in immunoglobulin genes. J Immunol. 2005;174:7781–7786. doi:10.4049/jimmunol.174.12.7781. PMID:15944281 PubMed DOI

Rogozin IB, Lada AG, Goncearenco A, et al. . Activation induced deaminase mutational signature overlaps with CpG methylation sites in follicular lymphoma and other cancers. Sci Rep. 2016;6:38133. doi:10.1038/srep38133. PMID:27924834 PubMed DOI PMC

Supek F, Lehner B. Clustered mutation signatures reveal that error-prone DNA repair targets mutations to active genes. Cell. 2017;170:534–547, e23. doi:10.1016/j.cell.2017.07.003. PMID:28753428 PubMed DOI

Li F, Mao G, Tong D, et al. . The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSalpha. Cell. 2013;153:590–600. doi:10.1016/j.cell.2013.03.025. PMID:23622243 PubMed DOI PMC

Frigola J, Sabarinathan R, Mularoni L, et al. . Reduced mutation rate in exons due to differential mismatch repair. Nat Genet. 2017;49:1684–1692. doi:10.1038/ng.3991. PMID:29106418 PubMed DOI PMC

Rogozin IB, Pavlov YI, Bebenek K, et al. . Somatic mutation hotspots correlate with DNA polymerase eta error spectrum. Nat Immunol. 2001;2:530–536. doi:10.1038/88732. PMID:11376340 PubMed DOI

Yeom M, Kim IH, Kim JK, et al. . Effects of twelve germline missense variations on DNA lesion and G-Quadruplex bypass activities of human DNA polymerase REV1. Chem Res Toxicol. 2016;29:367–379. doi:10.1021/acs.chemrestox.5b00513. PMID:26914252 PubMed DOI PMC

Sakiyama T, Kohno T, Mimaki S, et al. . Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk. Int J Cancer. 2005;114:730–737. doi:10.1002/ijc.20790. PMID:15609317 PubMed DOI

Xu HL, Gao XR, Zhang W, et al. . Effects of polymorphisms in translesion DNA synthesis genes on lung cancer risk and prognosis in Chinese men. Cancer Epidemiol. 2013;37:917–922. doi:10.1016/j.canep.2013.08.003. PMID:24012694 PubMed DOI PMC

Dai ZJ, Liu XH, Ma YF, et al. . Association between single nucleotide polymorphisms in DNA polymerase kappa gene and breast cancer risk in Chinese han population: a STROBE-compliant observational study. Medicine. 2016;95:e2466. doi:10.1097/MD.0000000000002466. PMID:26765445 PubMed DOI PMC

Yang J, Chen Z, Liu Y, et al. . 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. 2004;64:5597–5607. doi:10.1158/0008-5472.CAN-04-0603. PMID:15313897 PubMed DOI

Sasatani M, Xi Y, Kajimura J, et al. . Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level. Carcinogenesis. 2017;38:570–578. doi:10.1093/carcin/bgw208. PMID:28498946 PubMed DOI PMC

Albertella MR, Lau A, O'Connor MJ. The overexpression of specialized DNA polymerases in cancer. DNA Repair (Amst). 2005;4:583–593. doi:10.1016/j.dnarep.2005.01.005. PMID:15811630 PubMed DOI

Bavoux C, Leopoldino AM, Bergoglio V, et al. . Up-regulation of the error-prone DNA polymerase {kappa} promotes pleiotropic genetic alterations and tumorigenesis. Cancer Res. 2005;65:325–330. PMID:15665310 PubMed

Yuan F, Xu Z, Yang M, et al. . Overexpressed DNA polymerase iota regulated by JNK/c-Jun contributes to hypermutagenesis in bladder cancer. PloS One. 2013;8:e69317. doi:10.1371/journal.pone.0069317. PMID:23922701 PubMed DOI PMC

Wang H, Wu W, Wang HW, et al. . Analysis of specialized DNA polymerases expression in human gliomas: association with prognostic significance. Neuro Oncol. 2010;12:679–686. doi:10.1093/neuonc/nop074. PMID:20164241 PubMed DOI PMC

Ziv O, Zeisel A, Mirlas-Neisberg N, et al. . Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin. Nat Commun. 2014;5:5437. doi:10.1038/ncomms6437. PMID:25421715 PubMed DOI PMC

Despras E, Sittewelle M, Pouvelle C, et al. . Rad18-dependent SUMOylation of human specialized DNA polymerase eta is required to prevent under-replicated DNA. Nat Commun. 2016;7:13326. doi:10.1038/ncomms13326. PMID:27811911 PubMed DOI PMC

Garcia-Exposito L, Bournique E, Bergoglio V, et al. . Proteomic profiling reveals a specific role for translesion DNA polymerase eta in the alternative lengthening of telomeres. Cell Rep. 2016;17:1858–1871. doi:10.1016/j.celrep.2016.10.048. PMID:27829156 PubMed DOI PMC

Rey L, Sidorova JM, Puget N, et al. . Human DNA polymerase eta is required for common fragile site stability during unperturbed DNA replication. Mol Cell Biol. 2009;29:3344–3354. doi:10.1128/MCB.00115-09. PMID:19380493 PubMed DOI PMC

Bergoglio V, Boyer AS, Walsh E, et al. . DNA synthesis by Pol eta promotes fragile site stability by preventing under-replicated DNA in mitosis. J Cell Biol. 2013;201:395–408. doi:10.1083/jcb.201207066. PMID:23609533 PubMed DOI PMC

Bartkova J, Rezaei N, Liontos M, et al. . Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444:633–637. doi:10.1038/nature05268. PMID:17136093 PubMed DOI

Di Micco R, Fumagalli M, Cicalese A, et al. . Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006;444:638–642. doi:10.1038/nature05327. PMID:17136094 PubMed DOI

Bartek J, Bartkova J, Lukas J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene. 2007;26:7773–7779. doi:10.1038/sj.onc.1210881. PMID:18066090 PubMed DOI

Bartek J, Lukas J, Bartkova J. DNA damage response as an anti-cancer barrier: damage threshold and the concept of ‘conditional haploinsufficiency’. Cell Cycle. 2007;6:2344–2347. doi:10.4161/cc.6.19.4754. PMID:17700066 PubMed DOI

Bartkova J, Horejsi Z, Koed K, et al. . DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434:864–870. doi:10.1038/nature03482. PMID:15829956 PubMed DOI

Neelsen KJ, Zanini IM, Mijic S, et al. . Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template. Genes Dev. 2013;27:2537–2542. doi:10.1101/gad.226373.113. PMID:24298053 PubMed DOI PMC

Vaziri C, Saxena S, Jeon Y, et al. . A p53-dependent checkpoint pathway prevents rereplication. Mol Cell. 2003;11:997–1008. doi:10.1016/S1097-2765(03)00099-6. PMID:12718885 PubMed DOI

Jones RM, Mortusewicz O, Afzal I, et al. . Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress. Oncogene. 2013;32:3744–3753. doi:10.1038/onc.2012.387. PMID:22945645 PubMed DOI

Kotsantis P, Silva LM, Irmscher S, et al. . Increased global transcription activity as a mechanism of replication stress in cancer. Nat Commun. 2016;7:13087. doi:10.1038/ncomms13087. PMID:27725641 PubMed DOI PMC

Hamperl S, Bocek MJ, Saldivar JC, et al. . Transcription-replication conflict orientation modulates R-loop levels and activates distinct DNA damage responses. Cell. 2017;170:774–786, e19. PubMed PMC

Macheret M, Halazonetis TD. Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress. Nature. 2018;555:112–116. doi:10.1038/nature25507. PMID:29466339 PubMed DOI PMC

Irani K, Xia Y, Zweier JL, et al. . Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science. 1997;275:1649–1652. doi:10.1126/science.275.5306.1649. PMID:9054359 PubMed DOI

Lee AC, Fenster BE, Ito H, et al. . Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J Biol Chem. 1999;274:7936–7940. doi:10.1074/jbc.274.12.7936. PMID:10075689 PubMed DOI

Ogrunc M, Di Micco R, Liontos M, et al. . Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation. Cell Death Differ. 2014;21:998–1012. doi:10.1038/cdd.2014.16. PMID:24583638 PubMed DOI PMC

Vafa O, Wade M, Kern S, et al. . c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell. 2002;9:1031–1044. doi:10.1016/S1097-2765(02)00520-8. PMID:12049739 PubMed DOI

Moiseeva O, Bourdeau V, Roux A, et al. . Mitochondrial dysfunction contributes to oncogene-induced senescence. Mol Cell Biol. 2009;29:4495–507. doi:10.1128/MCB.01868-08. PMID:19528227 PubMed DOI PMC

Maya-Mendoza A, Ostrakova J, Kosar M, et al. . Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress. Molecular oncology. 2015;9:601–616. doi:10.1016/j.molonc.2014.11.001. PMID:25435281 PubMed DOI PMC

Bester AC, Roniger M, Oren YS, et al. . Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell. 2011;145:435–446. doi:10.1016/j.cell.2011.03.044. PMID:21529715 PubMed DOI PMC

Srinivasan SV, Dominguez-Sola D, Wang LC, et al. . Cdc45 is a critical effector of myc-dependent DNA replication stress. Cell Rep. 2013;3:1629–1639. doi:10.1016/j.celrep.2013.04.002. PMID:23643534 PubMed DOI PMC

Costantino L, Sotiriou SK, Rantala JK, et al. . Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science. 2014;343:88–91. doi:10.1126/science.1243211. PMID:24310611 PubMed DOI PMC

Gilad O, Nabet BY, Ragland RL, et al. . Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Res. 2010;70:9693–9702. doi:10.1158/0008-5472.CAN-10-2286. PMID:21098704 PubMed DOI PMC

Petta TB, Nakajima S, Zlatanou A, et al. . Human DNA polymerase iota protects cells against oxidative stress. Embo J. 2008;27:2883–2895. doi:10.1038/emboj.2008.210. PMID:18923427 PubMed DOI PMC

Watanabe T, Marotta M, Suzuki R, et al. . Impediment of replication forks by Long Non-coding RNA Provokes Chromosomal Rearrangements by Error-Prone Restart. Cell Rep. 2017;21:2223–2235. doi:10.1016/j.celrep.2017.10.103. PMID:29166612 PubMed DOI PMC

Neelsen KJ, Zanini IM, Herrador R, et al. . Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates. J Cell Biol. 2013;200:699–708. doi:10.1083/jcb.201212058. PMID:23479741 PubMed DOI PMC

Fikaris AJ, Lewis AE, Abulaiti A, et al. . Ras triggers ataxia-telangiectasia-mutated and Rad-3-related activation and apoptosis through sustained mitogenic signaling. J Biol Chem. 2006;281:34759–34767. doi:10.1074/jbc.M606737200. PMID:16968694 PubMed DOI

Daigaku Y, Davies AA, Ulrich HD. Ubiquitin-dependent DNA damage bypass is separable from genome replication. Nature. 2010;465:951–955. doi:10.1038/nature09097. PMID:20453836 PubMed DOI PMC

Betous R, Rey L, Wang G, et al. . Role of TLS DNA polymerases eta and kappa in processing naturally occurring structured DNA in human cells. Mol Carcinog. 2009;48:369–378. doi:10.1002/mc.20509. PMID:19117014 PubMed DOI PMC

Cea V, Cipolla L, Sabbioneda S. Replication of structured DNA and its implication in epigenetic stability. Front Genet. 2015;6:209. doi:10.3389/fgene.2015.00209. PMID:26136769 PubMed DOI PMC

Eddy S, Tillman M, Maddukuri L, et al. . Human translesion polymerase kappa exhibits enhanced activity and reduced fidelity two nucleotides from G-quadruplex DNA. Biochemistry. 2016;55(37):5218–5229. doi:10.1021/acs.biochem.6b00374. PMID:27525498 PubMed DOI PMC

Hile SE, Wang X, Lee MY, et al. . Beyond translesion synthesis: polymerase kappa fidelity as a potential determinant of microsatellite stability. Nucleic Acids Res. 2012;40:1636–1647. doi:10.1093/nar/gkr889. PMID:22021378 PubMed DOI PMC

Bartek J, Mistrik M, Bartkova J. Thresholds of replication stress signaling in cancer development and treatment. Nat Struct Mol Biol. 2012;19:5–7. doi:10.1038/nsmb.2220. PMID:22218289 PubMed DOI

Bi X, Barkley LR, Slater DM, et al. . Rad18 regulates DNA polymerase kappa and is required for recovery from S-phase checkpoint-mediated arrest. Mol Cell Biol. 2006;26:3527–3540. doi:10.1128/MCB.26.9.3527-3540.2006. PMID:16611994 PubMed DOI PMC

Bi X, Slater DM, Ohmori H, et al. . DNA polymerase kappa is specifically required for recovery from the benzo[a]pyrene-dihydrodiol epoxide (BPDE)-induced S-phase checkpoint. J Biol Chem. 2005;280:22343–22355. doi:10.1074/jbc.M501562200. PMID:15817457 PubMed DOI

Murga M, Campaner S, Lopez-Contreras AJ, et al. . Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat Struct Mol Biol. 2011;18:1331–1335. doi:10.1038/nsmb.2189. PMID:22120667 PubMed DOI PMC

Ceccaldi R, Liu JC, Amunugama R, et al. . Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature. 2015;518:258–262. doi:10.1038/nature14184. PMID:25642963 PubMed DOI PMC

Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7:573–584. doi:10.1038/nrc2167. PMID:17625587 PubMed DOI

Mamenta EL, Poma EE, Kaufmann WK, et al. . Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines. Cancer Res. 1994;54:3500–3505. PMID:8012973 PubMed

Kunz BA, Straffon AF, Vonarx EJ. DNA damage-induced mutation: tolerance via translesion synthesis. Mutat Res. 2000;451:169–185. doi:10.1016/S0027-5107(00)00048-8. PMID:10915871 PubMed DOI

Lehmann AR. Replication of damaged DNA by translesion synthesis in human cells. FEBS Lett. 2005;579:873–876. doi:10.1016/j.febslet.2004.11.029. PMID:15680966 PubMed DOI

Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481(7381):287–294. doi:10.1038/nature10760. PMID:22258607 PubMed DOI

Ummat A, Rechkoblit O, Jain R, et al. . Structural basis for cisplatin DNA damage tolerance by human polymerase eta during cancer chemotherapy. Nat Struct Mol Biol. 2012;19:628–632. doi:10.1038/nsmb.2295. PMID:22562137 PubMed DOI PMC

Alt A, Lammens K, Chiocchini C, et al. . Bypass of DNA lesions generated during anticancer treatment with cisplatin by DNA polymerase eta. Science. 2007;318:967–970. doi:10.1126/science.1148242. PMID:17991862 PubMed DOI

Chen YW, Cleaver JE, Hanaoka F, et al. . A novel role of DNA polymerase eta in modulating cellular sensitivity to chemotherapeutic agents. Mol Cancer Res. 2006;4:257–265. doi:10.1158/1541-7786.MCR-05-0118. PMID:16603639 PubMed DOI

Wagner JM, Karnitz LM. Cisplatin-induced DNA damage activates replication checkpoint signaling components that differentially affect tumor cell survival. Mol Pharmacol. 2009;76:208–214. doi:10.1124/mol.109.055178. PMID:19403702 PubMed DOI PMC

Yamashita YM, Okada T, Matsusaka T, et al. . RAD18 and RAD54 cooperatively contribute to maintenance of genomic stability in vertebrate cells. Embo J. 2002;21:5558–5566. doi:10.1093/emboj/cdf534. PMID:12374756 PubMed DOI PMC

Ceppi P, Novello S, Cambieri A, et al. . Polymerase eta mRNA expression predicts survival of non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res. 2009;15:1039–1045. doi:10.1158/1078-0432.CCR-08-1227. PMID:19188177 PubMed DOI

Teng KY, Qiu MZ, Li ZH, et al. . DNA polymerase eta protein expression predicts treatment response and survival of metastatic gastric adenocarcinoma patients treated with oxaliplatin-based chemotherapy. J Transl Med. 2010;8:126. doi:10.1186/1479-5876-8-126. PMID:21110884 PubMed DOI PMC

Ma CX, Janetka JW, Piwnica-Worms H. Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends Mol Med. 2011;17:88–96. doi:10.1016/j.molmed.2010.10.009. PMID:21087899 PubMed DOI PMC

Karnitz LM, Zou L. Molecular pathways: targeting ATR in cancer therapy. Clin Cancer Res. 2015;21:4780–4785. doi:10.1158/1078-0432.CCR-15-0479. PMID:26362996 PubMed DOI PMC

Brandsma I, Fleuren EDG, Williamson CT, et al. . Directing the use of DDR kinase inhibitors in cancer treatment. Expert Opin Investig Drugs. 2017;26:1341–1355. doi:10.1080/13543784.2017.1389895. PMID:28984489 PubMed DOI PMC

Toledo LI, Murga M, Zur R, et al. . A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol. 2011;18:721–727. doi:10.1038/nsmb.2076. PMID:21552262 PubMed DOI PMC

Reaper PM, Griffiths MR, Long JM, et al. . Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol. 2011;7:428–430. doi:10.1038/nchembio.573. PMID:21490603 PubMed DOI

Huntoon CJ, Flatten KS, Wahner Hendrickson AE, et al. . ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status. Cancer Res. 2013;73:3683–3691. doi:10.1158/0008-5472.CAN-13-0110. PMID:23548269 PubMed DOI PMC

Maher VM, Ouellette LM, Curren RD, et al. . Caffeine enhancement of the cytotoxic and mutagenic effect of ultraviolet irradiation in a xeroderma pigmentosum variant strain of human cells. Biochem Biophys Res Commun. 1976;71:228–234. doi:10.1016/0006-291X(76)90272-2. PMID:962915 PubMed DOI

Despras E, Daboussi F, Hyrien O, et al. . ATR/Chk1 pathway is essential for resumption of DNA synthesis and cell survival in UV-irradiated XP variant cells. Hum Mol Genet. 2010;19:1690–1701. doi:10.1093/hmg/ddq046. PMID:20123862 PubMed DOI

Mohni KN, Thompson PS, Luzwick JW, et al. . A synthetic lethal screen identifies DNA repair pathways that sensitize cancer cells to combined ATR inhibition and cisplatin treatments. PloS One. 2015;10:e0125482. doi:10.1371/journal.pone.0125482. PMID:25965342 PubMed DOI PMC

Sakurikar N, Thompson R, Montano R, et al. . A subset of cancer cell lines is acutely sensitive to the Chk1 inhibitor MK-8776 as monotherapy due to CDK2 activation in S phase. Oncotarget. 2016;7:1380–1394. doi:10.18632/oncotarget.6364. PMID:26595527 PubMed DOI PMC

RAD18 directs DNA double-strand break repair by homologous recombination to post-replicative chromatin