Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

DNA polymerases and cancer

Key Points

  • Fifteen DNA polymerases are encoded in mammalian genomes. Some function in the replication of the genome, but most participate in specialized DNA repair and DNA damage tolerance processes. The activity of these DNA polymerases will affect the response of a cell to DNA-damaging carcinogens and chemotherapeutic agents.

  • Some DNA polymerases catalyse DNA synthesis on damaged sites in DNA, helping cells tolerate DNA damage by translesion DNA synthesis (TLS). TLS polymerases are specialized for the bypass of different DNA adducts. Defects in Pol η (also known as POLH) are responsible for the variant type of xeroderma pigmentosum (XP-V).

  • Pol ζ (the catalytic subunit of which is REV3L) and REV1 are required for nearly all damage-induced base change mutagenesis in mammalian cells. Reduction of their activities sensitizes cells, including tumour cells, to DNA-damaging agents. However, chromosome rearrangements and inflammation can increase in the absence of these proteins, promoting carcinogenesis.

  • The expression of some genes encoding DNA polymerases may be altered in some cancers. In breast cancers, levels of POLQ (which encodes Pol θ) seem to be the most elevated compared with normal levels of expression. Comprehensive studies of DNA polymerase protein levels in cancer remain to be carried out.

  • The inhibition of DNA polymerase activities could be useful as an adjuvant to DNA-damaging therapies, and inhibitors for some polymerases have been found. Pharmacologically effective inhibitors highly specific for a single DNA polymerase remain to be identified.

  • Whole-genome analyses of cancers have not yet revealed cancer-associated alterations in DNA polymerase genes. It seems likely, however, that at least some cells in a tumour will have relevant alterations. Some DNA polymerases can be considered as tumour suppressors (Pol ζ, REV1, Pol η, Pol ι, Pol κ, Pol δ and Pol ɛ).

Abstract

There are 15 different DNA polymerases encoded in mammalian genomes, which are specialized for replication, repair or the tolerance of DNA damage. New evidence is emerging for lesion-specific and tissue-specific functions of DNA polymerases. Many point mutations that occur in cancer cells arise from the error-generating activities of DNA polymerases. However, the ability of some of these enzymes to bypass DNA damage may actually defend against chromosome instability in cells, and at least one DNA polymerase, Pol ζ, is a suppressor of spontaneous tumorigenesis. Because DNA polymerases can help cancer cells tolerate DNA damage, some of these enzymes might be viable targets for therapeutic strategies.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: DNA damage tolerance and carcinogenesis.
Figure 2: Strategies for translesion DNA synthesis.

References

  1. Waters, L. S. et al. Eukaryotic translesion polymerases and their roles and regulation in DNA damage tolerance. Microbiol Mol. Biol. Rev. 73, 134–154 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Bielas, J. H., Loeb, K. R., Rubin, B. P., True, L. D. & Loeb, L. A. Human cancers express a mutator phenotype. Proc. Natl Acad. Sci. USA 103, 18238–18242 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Chang, D. J. & Cimprich, K. A. DNA damage tolerance: when it's OK to make mistakes. Nature Chem. Biol. 5, 82–90 (2009).

    CAS  Article  Google Scholar 

  4. Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).

    CAS  PubMed  Article  Google Scholar 

  5. Hubscher, U., Maga, G. & Spadari, S. Eukaryotic DNA polymerases. Annu. Rev. Biochem. 71, 133–163 (2002).

    CAS  PubMed  Article  Google Scholar 

  6. Pursell, Z. F., Isoz, I., Lundstrom, E. B., Johansson, E. & Kunkel, T. A. Yeast DNA polymerase epsilon participates in leading-strand DNA replication. Science 317, 127–130 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. McCulloch, S. D. & Kunkel, T. A. The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res. 18, 148–161 (2008).

    CAS  PubMed  Article  Google Scholar 

  8. Schmitt, M. W., Matsumoto, Y. & Loeb, L. A. High fidelity and lesion bypass capability of human DNA polymerase delta. Biochimie 91, 1163–1172 (2009). A discussion of how a replicative DNA polymerase balances high fidelity at the expense of bypass activity.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. McCulloch, S. D. & Kunkel, T. A. The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res. 18, 148–161 (2008).

    CAS  PubMed  Article  Google Scholar 

  10. Goldsby, R. E. et al. High incidence of epithelial cancers in mice deficient for DNA polymerase delta proofreading. Proc. Natl Acad. Sci. USA 99, 15560–15565 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. Uchimura, A., Hidaka, Y., Hirabayashi, T., Hirabayashi, M. & Yagi, T. DNA polymerase delta is required for early mammalian embryogenesis. PLoS One 4, e4184 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. Albertson, T. M. et al. DNA polymerase epsilon and delta proofreading suppress discrete mutator and cancer phenotypes in mice. Proc. Natl Acad. Sci. USA 106, 17101–17104 (2009). References 11 and 12 show that loss of proofreading exonuclease activity in either Pol δ or Pol ɛ leads to an increase in spontaneous cancers. The types of cancers are different, suggesting tissue-specific requirements for DNA replication fidelity.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. Venkatesan, R. N. et al. Mutation at the polymerase active site of mouse DNA polymerase delta increases genomic instability and accelerates tumorigenesis. Mol. Cell Biol. 27, 7669–7682 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Flohr, T. et al. Detection of mutations in the DNA polymerase delta gene of human sporadic colorectal cancers and colon cancer cell lines. Int. J. Cancer 80, 919–929 (1999).

    CAS  PubMed  Article  Google Scholar 

  15. Daee, D. L., Mertz, T. M. & Shcherbakova, P. V. A cancer-associated DNA polymerase delta variant modeled in yeast causes a catastrophic increase in genomic instability. Proc. Natl Acad. Sci. USA 107, 157–162 (2010).

    CAS  PubMed  Article  Google Scholar 

  16. Loeb, L. A. & Monnat, R. J., Jr. DNA polymerases and human disease. Nature Rev. Genet. 9, 594–604 (2008).

    CAS  Article  PubMed  Google Scholar 

  17. Hübscher, U., Spadari, S., Villani, G. & Maga, G. DNA Polymerases: Discovery, characterization and functions in cellular DNA transactions (World Scientific, Singapore, 2010).

  18. Masutani, C. et al. Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity. EMBO J. 18, 3491–3501 (1999). Biochemical identification of Pol η as a DNA polymerase for the bypass of UV radiation-induced CPDs.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Inui, H. et al. Xeroderma pigmentosum-variant patients from America, Europe, and Asia. J. Invest. Dermatol. 128, 2055–2068 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Johnson, R. E., Washington, M. T., Prakash, S. & Prakash, L. Fidelity of human DNA polymerase eta. J. Biol. Chem. 275, 7447–7450 (2000).

    CAS  PubMed  Article  Google Scholar 

  21. Silverstein, T. D. et al. Structural basis for the suppression of skin cancers by DNA polymerase eta. Nature 465, 1039–1043 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Biertumpfel, C. et al. Structure and mechanism of human DNA polymerase eta. Nature 465, 1044–1048 (2010). References 21 and 22 provide a structural explanation for the efficient and error-avoiding bypass activity of Pol η for a CPD.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. Lin, Q. et al. Increased susceptibility to UV-induced skin carcinogenesis in polymerase eta-deficient mice. Cancer Res. 66, 87–94 (2006).

    CAS  PubMed  Article  Google Scholar 

  24. Limoli, C. L., Giedzinski, E., Bonner, W. M. & Cleaver, J. E. UV-induced replication arrest in the xeroderma pigmentosum variant leads to DNA double-strand breaks, γ-H2AX formation, and Mre11 relocalization. Proc. Natl Acad. Sci. USA 99, 233–238 (2002).

    CAS  PubMed  Article  Google Scholar 

  25. Auclair, Y., Rouget, R., Belisle, J. M., Costantino, S. & Drobetsky, E. A. Requirement for functional DNA polymerase eta in genome-wide repair of UV-induced DNA damage during S phase. DNA Repair (Amst) 9, 754–764 (2010).

    CAS  Article  Google Scholar 

  26. Rey, L. et al. Human DNA polymerase eta is required for common fragile site stability during unperturbed DNA replication. Mol. Cell Biol. 29, 3344–3354 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Glick, E. et al. Mutations in DNA polymerase eta are not detected in squamous cell carcinoma of the skin. Int. J. Cancer 119, 2225–2227 (2006).

    CAS  PubMed  Article  Google Scholar 

  28. Johnson, R. E., Haracska, L., Prakash, S. & Prakash, L. Role of DNA polymerase zeta in the bypass of a (6–4) TT photoproduct. Mol. Cell Biol. 21, 3558–3563 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Yamamoto, J. et al. Translesion synthesis across the (6–4) photoproduct and its Dewar valence isomer by the Y-family and engineered DNA polymerases. Nucleic Acids Symp. Ser. (Oxf.) 52, 339–340 (2008).

    CAS  Article  Google Scholar 

  30. Szuts, D., Marcus, A. P., Himoto, M., Iwai, S. & Sale, J. E. REV1 restrains DNA polymerase zeta to ensure frame fidelity during translesion synthesis of UV photoproducts in vivo. Nucleic Acids Res. 36, 6767–6780 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. Johnson, R. E., Washington, M. T., Haracska, L., Prakash, S. & Prakash, L. Eukaryotic polymerases iota and zeta act sequentially to bypass DNA lesions. Nature 406, 1015–1019 (2000).

    CAS  PubMed  Article  Google Scholar 

  32. Vaisman, A. et al. Sequence context-dependent replication of DNA templates containing UV-induced lesions by human DNA polymerase iota. DNA Repair (Amst) 2, 991–1006 (2003).

    CAS  Article  Google Scholar 

  33. Dumstorf, C. A. et al. 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 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. Ohkumo, T. et al. 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 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Wang, Y. et al. 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 (2007). References 33–35 show that both Pol h and Pol ι are important for defending against the carcinogenic effects of UV radiation.

    CAS  PubMed  Article  Google Scholar 

  36. Jarosz, D. F., Godoy, V. G., Delaney, J. C., Essigmann, J. M. & Walker, G. C. A single amino acid governs enhanced activity of DinB DNA polymerases on damaged templates. Nature 439, 225–228 (2006).

    PubMed  Article  Google Scholar 

  37. Minko, I. G. et al. Replication bypass of the acrolein-mediated deoxyguanine DNA-peptide cross-links by DNA polymerases of the DinB family. Chem. Res. Toxicol. 21, 1983–1990 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Minko, I. G. et al. Role for DNA polymerase kappa in the processing of N2-N2-guanine interstrand cross-links. J. Biol. Chem. 283, 17075–17082 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Ogi, T. et al. Expression of human and mouse genes encoding polkappa: testis-specific developmental regulation and AhR-dependent inducible transcription. Genes Cells 6, 943–953 (2001).

    CAS  PubMed  Article  Google Scholar 

  40. Ogi, T., Shinkai, Y., Tanaka, K. & Ohmori, H. Pol. kappa protects mammalian cells against the lethal and mutagenic effects of benzo[a]pyrene. Proc. Natl Acad. Sci. USA 99, 15548–15553 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Stancel, J. N. et al. Polk mutant mice have a spontaneous mutator phenotype. DNA Repair (Amst) 8, 1355–1362 (2009).

    CAS  Article  Google Scholar 

  42. Masutani, C., Kusumoto, R., Iwai, S. & Hanaoka, F. Mechanisms of accurate translesion synthesis by human DNA polymerase eta. EMBO J. 19, 3100–3109 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Colis, L. C., Raychaudhury, P. & Basu, A. K. Mutational specificity of gamma-radiation-induced guanine-thymine and thymine-guanine intrastrand cross-links in mammalian cells and translesion synthesis past the guanine-thymine lesion by human DNA polymerase eta. Biochemistry 47, 8070–8079 (2008).

    CAS  PubMed  Article  Google Scholar 

  44. Lee, D. H. & Pfeifer, G. P. Translesion synthesis of 7, 8-dihydro-8-oxo-2'-deoxyguanosine by DNA polymerase eta in vivo. Mutat. Res. 641, 19–26 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Minko, I. G. et al. Translesion synthesis past acrolein-derived DNA adduct, gamma -hydroxypropanodeoxyguanosine, by yeast and human DNA polymerase eta. J. Biol. Chem. 278, 784–790 (2003).

    CAS  Article  Google Scholar 

  46. Shachar, S. et al. Two-polymerase mechanisms dictate error-free and error-prone translesion DNA synthesis in mammals. EMBO J. 28, 383–393 (2009). The experiments show that different combinations of TLS DNA polymerases bypass lesions in mammalian cells, depending on the type of DNA damage. Bypass of most of the lesions tested was dependent on REV3L (the catalytic subunit of Pol ζ) and at least one additional DNA polymerase. The data fit a model in which DNA polymerases work sequentially to bypass adducts in DNA.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Albertella, M. R., Green, C. M., Lehmann, A. R. & O'Connor, M. J. A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. Cancer Res. 65, 9799–9806 (2005).

    CAS  PubMed  Article  Google Scholar 

  48. Betous, R. et al. Role of TLS DNA polymerases eta and kappa in processing naturally occurring structured DNA in human cells. Mol. Carcinog. 48, 369–378 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Obeid, S. et al. Replication through an abasic DNA lesion: structural basis for adenine selectivity. EMBO J. 29, 1738–1747 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Avkin, S., Adar, S., Blander, G. & Livneh, Z. Quantitative measurement of translesion replication in human cells: evidence for bypass of abasic sites by a replicative DNA polymerase. Proc. Natl Acad. Sci. USA 99, 3764–3769 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. Seki, M. et al. High-efficiency bypass of DNA damage by human DNA polymerase Q. EMBO J. 23, 4484–4494 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Arana, M. E., Seki, M., Wood, R. D., Rogozin, I. B. & Kunkel, T. A. Low-fidelity DNA synthesis by human DNA polymerase theta. Nucleic Acids Res. 36, 3847–3856 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Kusumoto, R., Masutani, C., Iwai, S. & Hanaoka, F. Translesion synthesis by human DNA polymerase eta across thymine glycol lesions. Biochemistry 41, 6090–6099 (2002).

    CAS  PubMed  Article  Google Scholar 

  54. Yoon, J. H., Bhatia, G., Prakash, S. & Prakash, L. Error-free replicative bypass of thymine glycol by the combined action of DNA polymerases kappa and zeta in human cells. Proc. Natl Acad. Sci. USA 107, 14116–14121 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. Marini, F., Kim, N., Schuffert, A. & Wood, R. D. POLN, a nuclear PolA family DNA polymerase homologous to the DNA cross-link sensitivity protein Mus308. J. Biol. Chem. 278, 32014–32019 (2003).

    CAS  PubMed  Article  Google Scholar 

  56. Takata, K. I., Shimizu, T., Iwai, S. & Wood, R. D. Human DNA polymerase N. (POLN) is a low-fidelity enzyme capable of error-free bypass of 5S-thymine glycol. J. Biol. Chem. 281, 23445–23455 (2006).

    CAS  PubMed  Article  Google Scholar 

  57. Takata, K. I., Arana, M. E., Seki, M., Kunkel, T. A. & Wood, R. D. Evolutionary conservation of residues in vertebrate DNA polymerase N conferring low fidelity and bypass activity. Nucleic Acids Res. 38, 3233–3244 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Yamanaka, K. et al. Novel Enzymatic Function of DNA Polymerase nu in Translesion DNA Synthesis Past Major Groove DNA-Peptide and DNA-DNA Cross-Links. Chem. Res. Toxicol. 23, 689–695 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Arana, M. E., Takata, K., Garcia-Diaz, M., Wood, R. D. & Kunkel, T. A. A unique error signature for human DNA polymerase ν. DNA Repair (Amst) 6, 213–223 (2007).

    CAS  Article  Google Scholar 

  60. Zietlow, L., Smith, L. A., Bessho, M. & Bessho, T. Evidence for the involvement of human DNA polymerase N. in the repair of DNA interstrand cross-links. Biochemistry 48, 11817–11824 (2009).

    CAS  PubMed  Article  Google Scholar 

  61. Moldovan, G. L. et al. DNA polymerase POLN participates in cross-link repair and homologous recombination. Mol. Cell Biol. 30, 1088–1096 (2010).

    CAS  PubMed  Article  Google Scholar 

  62. Yoshimura, M. et al. Vertebrate POLQ and POLbeta cooperate in base excision repair of oxidative DNA damage. Mol. Cell 24, 115–125 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Kohzaki, M. et al. DNA polymerases nu and theta are required for efficient immunoglobulin V gene diversification in chicken. J. Cell Biol. 189, 1117–1127 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Shivapurkar, N. et al. Multiple regions of chromosome 4 demonstrating allelic losses in breast carcinomas. Cancer Res. 59, 3576–3580 (1999).

    CAS  PubMed  Google Scholar 

  65. Holbeck, S. L. & Strathern, J. N. A role for REV3 in mutagenesis during double-strand break repair in Saccharomyces cerevisiae. Genetics 147, 1017–1024 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Abdulovic, A. L. & Jinks-Robertson, S. The in vivo characterization of translesion synthesis across UV-induced lesions in Saccharomyces cerevisiae: insights into Pol. zeta- and Pol. eta-dependent frameshift mutagenesis. Genetics 172, 1487–1498 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Hirano, Y. & Sugimoto, K. ATR homolog Mec1 controls association of DNA polymerase zeta-Rev1 complex with regions near a double-strand break. Curr. Biol. 16, 586–590 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. Gibbs, P. E., McGregor, W. G., Maher, V. M., Nisson, P. & Lawrence, C. W. A human homolog of the Saccharomyces cerevisiae REV3 gene, which encodes the catalytic subunit of DNA polymerase zeta. Proc. Natl Acad. Sci. USA 95, 6876–6880 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. Murakumo, Y. et al. Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7. J. Biol. Chem. 276, 35644–35651 (2001).

    CAS  Article  PubMed  Google Scholar 

  70. Jansen, J. G. et al. Mammalian polymerase zeta is essential for post-replication repair of UV-induced DNA lesions. DNA Repair (Amst) 8, 1444–1451 (2009).

    CAS  Article  Google Scholar 

  71. Takata, K. & Wood, R. D. Bypass specialists work together. EMBO J. 28, 313–314 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Bemark, M., Khamlichi, A. A., Davies, S. L. & Neuberger, M. S. Disruption of mouse polymerase zeta (Rev3) leads to embryonic lethality and impairs blastocyst development in vitro. Curr. Biol. 10, 1213–1216 (2000).

    CAS  PubMed  Article  Google Scholar 

  73. Esposito, G. et al. Disruption of the Rev3l-encoded catalytic subunit of polymerase zeta in mice results in early embryonic lethality. Curr. Biol. 10, 1221–1224 (2000).

    CAS  PubMed  Article  Google Scholar 

  74. Wittschieben, J. et al. Disruption of the developmentally regulated Rev3l gene causes embryonic lethality. Curr. Biol. 10, 1217–1220 (2000).

    CAS  PubMed  Article  Google Scholar 

  75. Van Sloun, P. P. et al. Involvement of mouse Rev3 in tolerance of endogenous and exogenous DNA damage. Mol. Cell Biol. 22, 2159–2169 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. O-Wang, J. et al. An essential role for REV3 in mammalian cell survival: absence of REV3 induces p53-independent embryonic death. Biochem. Biophys. Res. Commun. 293, 1132–1137 (2002).

    CAS  PubMed  Article  Google Scholar 

  77. Li, Z. et al. 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 (2002).

    CAS  PubMed  Article  Google Scholar 

  78. Diaz, M. et al. Decreased frequency and highly aberrant spectrum of ultraviolet-induced mutations in the hprt gene of mouse fibroblasts expressing antisense RNA to DNA polymerase zeta. Mol. Cancer Res. 1, 836–847 (2003).

    CAS  PubMed  Google Scholar 

  79. Sonoda, E. et al. Multiple roles of Rev3, the catalytic subunit of polzeta in maintaining genome stability in vertebrates. EMBO J. 22, 3188–3197 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Wu, F., Lin, X., Okuda, T. & Howell, S. B. DNA polymerase zeta regulates cisplatin cytotoxicity, mutagenicity, and the rate of development of cisplatin resistance. Cancer Res. 64, 8029–8035 (2004).

    CAS  PubMed  Article  Google Scholar 

  81. Okada, T. et al. Multiple roles of vertebrate REV genes in DNA repair and recombination. Mol. Cell Biol. 25, 6103–6111 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Wittschieben, J. P., Reshmi, S. C., Gollin, S. M. & Wood, R. D. Loss of DNA polymerase zeta causes chromosomal instability in mammalian cells. Cancer Res. 66, 134–142 (2006).

    CAS  PubMed  Article  Google Scholar 

  83. Gueranger, Q. et al. Role of DNA polymerases eta, iota and zeta in UV resistance and UV-induced mutagenesis in a human cell line. DNA Repair (Amst) 7, 1551–1562 (2008).

    CAS  Article  Google Scholar 

  84. Roos, W. P. et al. The translesion polymerase Rev3L in the tolerance of alkylating anticancer drugs. Mol. Pharmacol. 76, 927–934 (2009).

    CAS  PubMed  Article  Google Scholar 

  85. Wittschieben, J. P. et al. Loss of DNA polymerase zeta enhances spontaneous tumorigenesis. Cancer Res. 70, 2770–2778 (2010). Loss of Pol ζ provides a selective advantage for the formation of tumour cells, with enhanced spontaneous tumorigenesis in the presence and absence of p53 function.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Schenten, D. et al. Pol. zeta ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability. J. Exp. Med. 206, 477–490 (2009). B cells in which Rev3l is deleted display pronounced chromosome instability in mice.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Morelli, C. et al. Cloning and characterization of the common fragile site FRA6F harboring a replicative senescence gene and frequently deleted in human tumors. Oncogene 21, 7266–7276 (2002).

    CAS  PubMed  Article  Google Scholar 

  88. Nelson, J. R., Lawrence, C. W. & Hinkle, D. C. Thymine-thymine dimer bypass by yeast DNA polymerase zeta. Science 272, 1646–1649 (1996).

    CAS  PubMed  Article  Google Scholar 

  89. Lemontt, J. F. Mutants of Yeast Defective in Mutation Induced by Ultraviolet Light. Genetics 68, 21–33 (1971).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Simpson, L. J. & Sale, J. E. Rev1 is essential for DNA damage tolerance and non-templated immunoglobulin gene mutation in a vertebrate cell line. EMBO J. 22, 1654–1664 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Jansen, J. G. et al. The BRCT domain of mammalian Rev1 is involved in regulating DNA translesion synthesis. Nucleic Acids Res. 33, 356–365 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Jansen, J. G. et al. Separate domains of Rev1 mediate two modes of DNA damage bypass in mammalian cells. Mol. Cell Biol. 29, 3113–3123 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Jansen, J. G. et al. Strand-biased defect in C/G transversions in hypermutating immunoglobulin genes in Rev1-deficient mice. J. Exp. Med. 203, 319–323 (2006).

    PubMed  PubMed Central  Article  Google Scholar 

  94. Masuda, K. et al. A critical role for REV1 in regulating the induction of C:G. transitions and A:T mutations during Ig gene hypermutation. J. Immunol. 183, 1846–1850 (2009).

    CAS  PubMed  Article  Google Scholar 

  95. Tsaalbi-Shtylik, A. et al. Error-prone translesion replication of damaged DNA suppresses skin carcinogenesis by controlling inflammatory hyperplasia. Proc. Natl Acad. Sci. USA 106, 21836–21841 (2009). Partial ablation of REV1 function sensitizes cells to UV radiation and greatly increases carcinogenic inflammation.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. Lin, W. et al. The human REV1 gene codes for a DNA template-dependent dCMP transferase. Nucleic Acids Res. 27, 4468–4475 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Hlavin, E. M., Smeaton, M. B., Noronha, A. M., Wilds, C. J. & Miller, P. S. Cross-link structure affects replication-independent DNA interstrand cross-link repair in mammalian cells. Biochemistry 49, 3977–3988 (2010).

    CAS  PubMed  Article  Google Scholar 

  98. Ross, A. L., Simpson, L. J. & Sale, J. E. Vertebrate DNA damage tolerance requires the C-terminus but not BRCT or transferase domains of REV1. Nucleic Acids Res. 33, 1280–1289 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Lehmann, A. R. et al. Translesion synthesis: Y-family polymerases and the polymerase switch. DNA Repair (Amst) 6, 891–899 (2007).

    CAS  Article  Google Scholar 

  100. Andersen, P. L., Xu, F. & Xiao, W. Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA. Cell Res. 18, 162–173 (2007).

    Article  CAS  Google Scholar 

  101. Terai, K., Abbas, T., Jazaeri, A. A. & Dutta, A. CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis. Mol. Cell 37, 143–149 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Bienko, M. et al. Regulation of translesion synthesis DNA polymerase eta by monoubiquitination. Mol. Cell 37, 396–407 (2010).

    CAS  Article  PubMed  Google Scholar 

  103. Pastushok, L., Hanna, M. & Xiao, W. Constitutive fusion of ubiquitin to PCNA provides DNA damage tolerance independent of translesion polymerase activities. Nucleic Acids Res. 28, 5047–5058 (2010).

    Article  CAS  Google Scholar 

  104. Guo, C. et al. Mouse Rev1 protein interacts with multiple DNA polymerases involved in translesion DNA synthesis. EMBO J. 22, 6621–6630 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Ohashi, E. et al. Interaction of hREV1 with three human Y-family DNA polymerases. Genes Cells 9, 523–531 (2004).

    CAS  Article  PubMed  Google Scholar 

  106. Yuasa, M. S. et al. 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 (2006).

    CAS  PubMed  Article  Google Scholar 

  107. Ohashi, E. et al. Identification of a novel REV1-interacting motif necessary for DNA polymerase kappa function. Genes Cells 14, 101–111 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Guo, C. et al. REV1 protein interacts with PCNA: significance of the REV1 BRCT domain in vitro and in vivo. Mol. Cell 23, 265–271 (2006).

    CAS  Article  PubMed  Google Scholar 

  109. Edmunds, C. E., Simpson, L. J. & Sale, J. E. PCNA ubiquitination and REV1 define temporally distinct mechanisms for controlling translesion synthesis in the avian cell line DT40. Mol. Cell 30, 519–529 (2008).

    CAS  Article  PubMed  Google Scholar 

  110. McCulloch, S. D., Kokoska, R. J. & Kunkel, T. A. Efficiency, fidelity and enzymatic switching during translesion DNA synthesis. Cell Cycle 3, 580–583 (2004).

    CAS  PubMed  Article  Google Scholar 

  111. Ogawara, D. et al. Near-full-length REV3L appears to be a scarce maternal factor in Xenopus laevis eggs that changes qualitatively in early embryonic development. DNA Repair (Amst) 9, 90–95 (2010). A quantitative assessment of the abundance of DNA polymerases in Xenopus laevis eggs, showing that TLS DNA polymerases have low abundance, particularly Pol ζ.

    CAS  Article  Google Scholar 

  112. Lopes, M., Foiani, M. & Sogo, J. M. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. Mol. Cell 21, 15–27 (2006). Molecular and genetic analysis of the interplay between TLS, strand switching and recombination at a site of DNA damage.

    CAS  PubMed  Article  Google Scholar 

  113. Daigaku, Y., Davies, A. A. & Ulrich, H. D. Ubiquitin-dependent DNA damage bypass is separable from genome replication. Nature 465, 951–955 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Daigaku, Y., Davies, A. A. & Ulrich, H. D. Ubiquitin-dependent DNA damage bypass is separable from genome replication. Nature 465, 951–955 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Waters, L. S. & Walker, G. C. The critical mutagenic translesion DNA polymerase Rev1 is highly expressed during G2/M phase rather than S phase. Proc. Natl Acad. Sci. USA 103, 8971–8976 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. Putnam, C. D., Hayes, T. K. & Kolodner, R. D. Post-replication repair suppresses duplication-mediated genome instability. PLoS Genet. 6, e1000933 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. Karras, G. I. & Jentsch, S. The RAD6 DNA damage tolerance pathway operates uncoupled from the replication fork and is functional beyond S. phase. Cell 141, 255–267 (2010).

    CAS  Article  PubMed  Google Scholar 

  118. Almeida, K. H. & Sobol, R. W. A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification. DNA Repair (Amst) 6, 695–711 (2007).

    CAS  Article  Google Scholar 

  119. Copeland, W. C. The mitochondrial DNA polymerase in health and disease. Subcell. Biochem. 50, 211–222 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Starcevic, D., Dalal, S. & Sweasy, J. B. Is there a link between DNA polymerase beta and cancer? Cell Cycle 3, 998–1001 (2004).

    CAS  PubMed  Article  Google Scholar 

  121. Sweasy, J. B. et al. Expression of DNA polymerase β cancer-associated variants in mouse cells results in cellular transformation. Proc. Natl Acad. Sci. USA 102, 14350–14355 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. Cabelof, D. C. et al. Haploinsufficiency in DNA polymerase beta increases cancer risk with age and alters mortality rate. Cancer Res. 66, 7460–7465 (2006).

    CAS  PubMed  Article  Google Scholar 

  123. Bebenek, K. et al. 5′-Deoxyribose phosphate lyase activity of human DNA polymerase iota in vitro. Science 291, 2156–2159 (2001).

    CAS  PubMed  Article  Google Scholar 

  124. Braithwaite, E. K. et al. DNA polymerase lambda mediates a back-up base excision repair activity in extracts of mouse embryonic fibroblasts. J. Biol. Chem. 280, 18469–18475 (2005).

    CAS  PubMed  Article  Google Scholar 

  125. Prasad, R. et al. Human DNA polymerase θ possesses 5'-dRP lyase activity and functions in single-nucleotide base excision repair in vitro. Nucleic Acids Res. 37, 1868–1877 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. Petta, T. B. et al. Human DNA polymerase iota protects cells against oxidative stress. EMBO J. 27, 2883–2895 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Prasad, R. et al. Localization of the deoxyribose phosphate lyase active site in human DNA polymerase iota by controlled proteolysis. J. Biol. Chem. 278, 29649–29654 (2003).

    CAS  PubMed  Article  Google Scholar 

  128. van Loon, B., Markkanen, E. & Hubscher, U. Oxygen as a friend and enemy: How to combat the mutational potential of 8-oxo-guanine. DNA Repair (Amst) 9, 604–616 (2010).

    CAS  Article  Google Scholar 

  129. Goff, J. P. et al. Lack of DNA polymerase theta (POLQ) radiosensitizes bone marrow stromal cells in vitro and increases reticulocyte micronuclei after total-body irradiation. Radiation Research 172, 165–174 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Shivji, M. K., Podust, V. N., Hubscher, U. & Wood, R. D. Nucleotide excision repair DNA synthesis by DNA polymerase epsilon in the presence of PCNA, RFC, and RPA. Biochemistry 34, 5011–5017 (1995).

    CAS  PubMed  Article  Google Scholar 

  131. Ogi, T. et al. Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells. Mol. Cell 37, 714–727 (2010).

    CAS  Article  PubMed  Google Scholar 

  132. Friedberg, E. C. et al. DNA repair and mutagenesis, 2nd edition (ASM Press, Washington, DC, 2006).

  133. Kidane, D. et al. DNA polymerase beta is critical for mouse meiotic synapsis. EMBO J. 29, 410–423 (2010).

    CAS  PubMed  Article  Google Scholar 

  134. Kawamoto, T. et al. Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis. Mol. Cell 20, 793–799 (2005).

    CAS  PubMed  Article  Google Scholar 

  135. McIlwraith, M. J. & West, S. C. DNA repair synthesis facilitates RAD52-mediated second-end capture during DSB repair. Mol. Cell 29, 510–516 (2008).

    CAS  PubMed  Article  Google Scholar 

  136. Rattray, A. J., Shafer, B. K., McGill, C. B. & Strathern, J. N. The roles of REV3 and RAD57 in double-strand-break-repair-induced mutagenesis of Saccharomyces cerevisiae. Genetics 162, 1063–1077 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Shen, X. et al. REV3 and REV1 play major roles in recombination-independent repair of DNA interstrand cross-links mediated by monoubiquitinated proliferating cell nuclear antigen (PCNA). J. Biol. Chem. 281, 13869–13872 (2006).

    CAS  PubMed  Article  Google Scholar 

  138. Zhang, N., Liu, X., Li, L. & Legerski, R. Double-strand breaks induce homologous recombinational repair of interstrand cross-links via cooperation of MSH2, ERCC1-XPF, REV3, and the Fanconi anemia pathway. DNA Repair (Amst) 6, 1670–1678 (2007).

    CAS  Article  Google Scholar 

  139. Mahajan, K. N. et al. Association of terminal deoxynucleotidyl transferase with Ku. Proc. Natl Acad. Sci. USA 96, 13926–13931 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  140. Ma, Y. et al. A biochemically defined system for mammalian nonhomologous DNA end joining. Mol. Cell 16, 701–713 (2004).

    CAS  PubMed  Article  Google Scholar 

  141. Bebenek, K., Garcia-Diaz, M., Zhou, R. Z., Povirk, L. F. & Kunkel, T. A. Loop 1 modulates the fidelity of DNA polymerase λ. Nucleic Acids Res. 38, 5419–5431 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Andrade, P., Martin, M. J., Juarez, R., Lopez de Saro, F. & Blanco, L. Limited terminal transferase in human DNA polymerase mu defines the required balance between accuracy and efficiency in NHEJ. Proc. Natl Acad. Sci. USA 106, 16203–16208 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. Desiderio, S. V. et al. Insertion of N. regions into heavy-chain genes is correlated with expression of terminal deoxytransferase in B cells. Nature 311, 752–755 (1984).

    CAS  PubMed  Article  Google Scholar 

  144. Bertocci, B., De Smet, A., Weill, J. C. & Reynaud, C. A. Nonoverlapping functions of DNA polymerases mu, lambda, and terminal deoxynucleotidyltransferase during immunoglobulin V(D)J recombination in vivo. Immunity 25, 31–41 (2006).

    CAS  PubMed  Article  Google Scholar 

  145. Lucas, D. et al. Altered hematopoiesis in mice lacking DNA polymerase mu is due to inefficient double-strand break repair. PLoS Genet. 5, e1000389 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  146. Chayot, R., Danckaert, A., Montagne, B. & Ricchetti, M. Lack of DNA polymerase mu affects the kinetics of DNA double-strand break repair and impacts on cellular senescence. DNA Repair (Amst) 9, 1187–1199 (2010).

    CAS  Article  Google Scholar 

  147. Bertocci, B., De Smet, A., Berek, C., Weill, J. C. & Reynaud, C. A. Immunoglobulin kappa light chain gene rearrangement is impaired in mice deficient for DNA polymerase mu. Immunity 19, 203–211 (2003).

    CAS  PubMed  Article  Google Scholar 

  148. Higgins, G. S. et al. A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown. Cancer Res. 70, 2984–2993 (2010). POLQ is identified as a gene conferring radioprotection to human tumour cells.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. Shima, N., Munroe, R. J. & Schimenti, J. C. The mouse genomic instability mutation chaos1 is an allele of Polq that exhibits genetic interaction with Atm. Mol. Cell Biol. 24, 10381–10389 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. Yu, A. M. & McVey, M. Synthesis-dependent microhomology-mediated end joining accounts for multiple types of repair junctions. Nucleic Acids Res. (2010).

  151. Chan, S. H., Yu, A. M. & McVey, M. Dual Roles for DNA polymerase theta in alternative end-joining repair of double-strand breaks in Drosophila. PLoS Genet. 6, e1001005 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  152. Brondello, J. M. et al. Novel evidences for a tumor suppressor role of Rev3, the catalytic subunit of Pol zeta. Oncogene 27, 6093–6101 (2008).

    CAS  PubMed  Article  Google Scholar 

  153. Pan, Q., Fang, Y., Xu, Y., Zhang, K. & Hu, X. Down-regulation of DNA polymerases kappa, eta, iota, and zeta in human lung, stomach, and colorectal cancers. Cancer Lett. 217, 139–147 (2005).

    CAS  PubMed  Article  Google Scholar 

  154. Lemée, F. et al. POLQ up-regulation is associated with poor survival in breast cancer, perturbs DNA replication and promotes genetic instability Proc. Natl Acad. Sci. (USA) 107, 13390–13395 (2010). A screen showing that POLQ expression is enhanced in breast cancer samples compared with normal tissue.

    Article  Google Scholar 

  155. Albertella, M. R., Lau, A. & O'Connor, M. J. The overexpression of specialized DNA polymerases in cancer. DNA Repair (Amst) 4, 583–593 (2005).

    CAS  Article  Google Scholar 

  156. O-Wang, J. et al. DNA polymerase kappa, implicated in spontaneous and DNA damage-induced mutagenesis, is overexpressed in lung cancer. Cancer Res. 61, 5366–5369 (2001).

    CAS  PubMed  Google Scholar 

  157. Wang, H. et al. Analysis of specialized DNA polymerases expression in human gliomas: association with prognostic significance. Neuro Oncol. 12, 679–686 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. Liu, P. Y. et al. Identification of Las2, a major modifier gene affecting the Pas1 mouse lung tumor susceptibility locus. Cancer Res. 69, 6290–6298 (2009).

    CAS  PubMed  Article  Google Scholar 

  159. Ceppi, P. et al. Polymerase eta mRNA expression predicts survival of non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin. Cancer Res. 15, 1039–1045 (2009).

    CAS  PubMed  Article  Google Scholar 

  160. Tan, X. H. et al. Frequent mutation related with overexpression of DNA polymerase beta in primary tumors and precancerous lesions of human stomach. Cancer Lett. 220, 101–114 (2005).

    CAS  PubMed  Article  Google Scholar 

  161. Yoshizawa, K. et al. Gastrointestinal hyperplasia with altered expression of DNA polymerase beta. PLoS One 4, e6493 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  162. Pillaire, M. J. et al. Upregulation of error-prone DNA polymerases beta and kappa slows down fork progression without activating the replication checkpoint. Cell Cycle 6, 471–477 (2007).

    CAS  PubMed  Article  Google Scholar 

  163. Chan, K. et al. Overexpression of DNA polymerase beta results in an increased rate of frameshift mutations during base excision repair. Mutagenesis 22, 183–188 (2007).

    CAS  PubMed  Article  Google Scholar 

  164. Kawamura, K. et al. DNA polymerase θ is preferentially expressed in lymphoid tissues and upregulated in human cancers. Int. J. Cancer 109, 9–16 (2004).

    CAS  PubMed  Article  Google Scholar 

  165. Pillaire, M. J. et al. A 'DNA replication' signature of progression and negative outcome in colorectal cancer. Oncogene 29, 876–887 (2010).

    CAS  PubMed  Article  Google Scholar 

  166. Higgins, G. S. et al. Overexpression of POLQ confers a poor prognosis in early breast cancer patients. Oncotarget 1, 175–184 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  167. Kuriyama, I. et al. Effect of dehydroaltenusin-C12 derivative, a selective DNA polymerase alpha inhibitor, on DNA replication in cultured cells. Molecules 13, 2948–2961 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. Kuramochi, K. et al. Synthesis and structure-activity relationships of dehydroaltenusin derivatives as selective DNA polymerase alpha inhibitors. Bioorg Med. Chem. 17, 7227–7238 (2009).

    CAS  PubMed  Article  Google Scholar 

  169. Maeda, N. et al. Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase alpha. Biochem. Biophys. Res. Commun. 352, 390–396 (2007).

    CAS  PubMed  Article  Google Scholar 

  170. Kumamoto-Yonezawa, Y. et al. Enhancement of human cancer cell radiosensitivity by conjugated eicosapentaenoic acid - a mammalian DNA polymerase inhibitor. Int. J. Oncol. 36, 577–584 (2010).

    CAS  PubMed  Google Scholar 

  171. Mizushina, Y. et al. The inhibitory action of kohamaic acid A derivatives on mammalian DNA polymerase beta. Molecules 14, 102–121 (2009).

    CAS  Article  Google Scholar 

  172. Gao, Z., Maloney, D. J., Dedkova, L. M. & Hecht, S. M. Inhibitors of DNA polymerase beta: activity and mechanism. Bioorg Med. Chem. 16, 4331–4340 (2008).

    CAS  PubMed  Article  Google Scholar 

  173. Stachelek, G. C. et al. Potentiation of temozolomide cytotoxicity by inhibition of DNA polymerase beta is accentuated by BRCA2 mutation. Cancer Res. 70, 409–417 (2010).

    CAS  PubMed  Article  Google Scholar 

  174. Jaiswal, A. S. et al. A novel inhibitor of DNA polymerase beta enhances the ability of temozolomide to impair the growth of colon cancer cells. Mol. Cancer Res. 7, 1973–1983 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. Yang, J. et al. Cells deficient in the base excision repair protein, DNA polymerase beta, are hypersensitive to oxaliplatin chemotherapy. Oncogene 29, 463–468 (2010).

    CAS  PubMed  Article  Google Scholar 

  176. Mizushina, Y. et al. 3-O-methylfunicone, a selective inhibitor of mammalian Y-family DNA polymerases from an Australian sea salt fungal strain. Mar. Drugs 7, 624–639 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. Dorjsuren, D. et al. A real-time fluorescence method for enzymatic characterization of specialized human DNA polymerases. Nucleic Acids Res. 37, e128 (2009). Describes an example of an assay for a small-molecule inhibitor and reports nanomolar inhibitors of Pol ι and Pol η.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  178. Dumstorf, C. A., Mukhopadhyay, S., Krishnan, E., Haribabu, B. & McGregor, W. G. REV1 is implicated in the development of carcinogen-induced lung cancer. Mol. Cancer Res. 7, 247–254 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. Xie, K., Doles, J., Hemann, M. T. & Walker, G. C. Error-prone translesion synthesis mediates acquired chemoresistance. Proc. Natl Acad. Sci. USA 107, 20792–20797 (2010). In a mouse cancer model, the activity of REV1 in mutagenesis has a crucial role in the development of acquired resistance to cyclophosphamide.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  180. Doles, J. et al. Suppression of Rev3, the catalytic subunit of Pol z, sensitizes drug-resistant lung tumors to chemotherapy. Proc. Natl Acad. Sci. USA 107, 20786–20791 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  181. Swan, M. K., Johnson, R. E., Prakash, L., Prakash, S. & Aggarwal, A. K. Structure of the human Rev1-DNA-dNTP ternary complex. J. Mol. Biol. 390, 699–709 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. Nair, D. T., Johnson, R. E., Prakash, S., Prakash, L. & Aggarwal, A. K. Replication by human DNA polymerase-iota occurs by Hoogsteen base-pairing. Nature 430, 377–380 (2004).

    CAS  PubMed  Article  Google Scholar 

  183. Lemée, F. et al. POLQ up-regulation is associated with poor survival in breast cancer, perturbs DNA replication and promotes genetic instability Proc. Natl Acad. Sci. USA 107, 13390–13395 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  184. Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).

    CAS  Article  PubMed  Google Scholar 

  185. Bhagwat, N. R. et al. Immunodetection of DNA repair endonuclease ERCC1-XPF in human tissue. Cancer Res. 69, 6831–6838 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. King, N. M. et al. Overproduction of DNA polymerase eta does not raise the spontaneous mutation rate in diploid human fibroblasts. DNA Repair (Amst) 4, 714–724 (2005).

    CAS  Article  Google Scholar 

  187. Ohmori, H., Hanafusa, T., Ohashi, E., Vaziri, C. Separate Roles of Structured and Unstructured Regions of Y-Family DNA Polymerases. Adv. in Prot.Chem. and Struc. Biol. 78, 99–146 (2009).

    CAS  Google Scholar 

  188. Boudsocq, F. et al. Investigating the role of the little finger domain of Y-family DNA polymerases in low fidelity synthesis and translesion replication. J. Biol. Chem. 279, 32932–32940 (2004).

    CAS  PubMed  Article  Google Scholar 

  189. Betz, K. et al. Structures of DNA polymerases caught processing size-augmented nucleotide probes. Angew. Chem. Int. Ed Engl. 49, 5181–5184 (2010).

    CAS  PubMed  Article  Google Scholar 

  190. Zeng, X. et al. DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nature Immunol. 2, 537–541 (2001).

    CAS  Article  Google Scholar 

  191. Delbos, F., Aoufouchi, S., Faili, A., Weill, J. C. & Reynaud, C. A. DNA polymerase eta is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse. J. Exp. Med. 204, 17–23 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  192. Martomo, S. A., Saribasak, H., Yokoi, M., Hanaoka, F. & Gearhart, P. J. Reevaluation of the role of DNA polymerase theta in somatic hypermutation of immunoglobulin genes. DNA Repair (Amst) 7, 1603–1608 (2008).

    CAS  PubMed Central  Article  Google Scholar 

  193. Ross, A. L. & Sale, J. E. The catalytic activity of REV1 is employed during immunoglobulin gene diversification in DT40. Mol. Immunol. 43, 1587–1594 (2006).

    CAS  PubMed  Article  Google Scholar 

  194. Hance, N., Ekstrand, M. I. & Trifunovic, A. Mitochondrial DNA polymerase gamma is essential for mammalian embryogenesis. Hum. Mol. Genet. 14, 1775–1783 (2005).

    CAS  PubMed  Article  Google Scholar 

  195. Gu, H., Marth, J. D., Orban, P. C., Mossmann, H. & Rajewsky, K. Deletion of a DNA polymerase β gene segment in T cells using cell type-specific gene targeting. Science 265, 103–106 (1994).

    CAS  PubMed  Article  Google Scholar 

  196. Sugo, N., Aratani, Y., Nagashima, Y., Kubota, Y. & Koyama, H. Neonatal lethality with abnormal neurogenesis in mice deficient in DNA polymerase beta. EMBO J. 19, 1397–1404 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. Sugo, N., Niimi, N., Aratani, Y., Takiguchi-Hayashi, K. & Koyama, H. p53 Deficiency rescues neuronal apoptosis but not differentiation in DNA polymerase beta-deficient mice. Mol. Cell Biol. 24, 9470–9477 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  198. Delbos, F. et al. Contribution of DNA polymerase eta to immunoglobulin gene hypermutation in the mouse. J. Exp. Med. 201, 1191–1196 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. McDonald, J. P. et al. 129-derived strains of mice are deficient in DNA polymerase iota and have normal immunoglobulin hypermutation. J. Exp. Med. 198, 635–643 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. Schenten, D. et al. DNA polymerase kappa deficiency does not affect somatic hypermutation in mice. Eur. J. Immunol. 32, 3152–3160 (2002).

    CAS  PubMed  Article  Google Scholar 

  201. Shima, N. et al. Phenotype-based identification of mouse chromosome instability mutants. Genetics 163, 1031–1040 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. Friedberg, E. C. & Meira, L. B. Database of mouse strains carrying targeted mutations in genes affecting biological responses to DNA damage Version 7. DNA Repair (Amst) 5, 189–209 (2006).

    CAS  Article  Google Scholar 

  203. Berdis, A. DNA polymerases as therapeutic targets. Biochemistry 47, 8253–8260 (2008)

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

Research on DNA polymerases by the authors is supported by US National Institutes of Health (NIH) grants CA09717 and CA132840 from the National Cancer Institute, by grant P30ES007784 from the National Institute of Environmental Health Sciences and by NIH Cancer Center Support Grant P30-CA016672 (University of Texas MD Anderson Cancer Center, USA).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard D. Wood.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary

bleomycin

cisplatin

cyclophosphamide

eicosapentaenoic acid

etoposide

hydroxyurea

mitomycin C

oxaliplatin

temozolomide

FURTHER INFORMATION

Human DNA Repair Genes

Glossary

DNA damage

A term that encompasses the many types of chemical alterations that can change the structure of DNA. Damage can be caused by reactions that disrupt bonds in the nucleobases, the deoxyribose sugar ring, or the phosphate groups of DNA or by the addition of chemical moieties such as hydroxyl groups, methyl groups, or even bulkier groups derived from polycyclic molecules. Such additions are often referred to as DNA adducts. DNA damage is already plural, so DNA damages is incorrect, an alternative is DNA lesions.

Template switching

An error-avoiding strategy for DNA damage tolerance that uses the newly synthesized, undamaged strand of a sister chromatid for bypass replication.

Checkpoint

A control mechanism to verify whether each phase of the cell cycle has been completed accurately. If DNA damage is present, some checkpoint controls prevent or delay progression through the cell cycle, for example from G1 to S phase or from G2 phase to mitosis.

Leading and lagging strands

DNA synthesis can only add nucleotides to the terminal 3′-OH group of a growing polymer. The strand synthesized continuously during DNA replication is the leading strand. The strand of DNA that is synthesized in discontinuous segments is the lagging strand.

Exonuclease

An exonuclease cleaves DNA phosphodiester bonds to release nucleotides from one end of a polynucleotide chain. DNA polymerases synthesize DNA in a 5′–3′ direction and some DNA polymerases have an intrinsic 3′–5′ exonuclease activity that enables proofreading of their own mistakes.

Y-family

The prototypes for Y-family polymerases are the Escherichia coli TLS DNA polymerases DinB (Pol IV) and UmuC (Pol V).

B-family

B-family DNA polymerases show similarity to E. coli Pol II.

A-family

The A-family DNA polymerase domain is similar to E. coli DNA polymerase I (Pol I), encoded by the bacterial PolA gene.

Xeroderma pigmentosum

An inherited human syndrome characterized by severe photosensitivity, a high incidence of skin cancer and neurological abnormalities. The disorder is caused by a deficiency in NER genes (XPA-XPG), or in TLS past UV radiation-induced DNA damage (the XP-V type is caused by mutations in POLH).

Cyclobutane pyrimidine dimer

(CPD). The most frequent UV radiation-induced DNA lesion, formed by the covalent linkage of the C5 and C6 bonds of adjacent pyrimidines to form a cyclobutane ring, without directly altering the base pairing faces of the dimerized bases. Such dimers are formed most commonly between adjacent thymines, but also between thymine and cytosine or two adjacent cytosines.

Fragile site

Heritable regions on chromosomes that are associated with an increased frequency of chromosome breaks, gaps and other aberrations. Fragile sites, and the genes that they contain, are frequently rearranged or deleted in cancer cells.

(6-4) photoproduct

The second most common type of UV radiation-induced DNA damage, involving linkage of the C6 position of a 5′ pyrimidine base to the C4 position of a 3′ adjacent pyrimidine base. (6-4) photoproducts distort the DNA helix more than a CPD and form most often at 5′ thymine-cytosine-3′ sequences.

Abasic site

A site in a DNA chain that is missing a pyrimidine or purine base residue, but where the phosphodiester backbone remains intact. Such sites can arise when a base–sugar bond is cleaved by a DNA glycosylase during BER, or by a spontaneous hydrolytic reaction.

Interstrand crosslink

(ICL). Covalently links the two complementary strands of duplex DNA. Such crosslinks are formed by some carcinogenic and chemotherapeutic agents and they are especially toxic because they block the complementary DNA strand separation that is necessary for DNA replication and transcription.

Sliding clamp

A mobile platform for DNA replication and repair machinery. The eukaryotic sliding clamp PCNA binds to DNA polymerases and is crucial for the switching of polymerases during TLS and DNA repair.

X-family

X-family polymerases in mammalian cells are Pol β, Pol λ, Pol μ and TDT.

Hydrolytic reactions

Decomposition of a chemical compound or a molecular bond by reaction with water.

Alkylating agent

An electrophilic compound that can covalently add an alkyl group to a DNA base, or to other biological macromolecules. These compounds act as both carcinogens (for example, methyl chloride) and as chemotherapeutic agents (for example, mechloroethamine).

Nonsense mutation

A change in the codon for an amino acid to a stop codon. Nonsense mutations cause protein truncation and often nonsense-mediated decay of the encoding mRNA.

Terminal deoxynucleotidyl-transferase

(TDT). A template-independent DNA synthesis activity that catalyses the addition of nucleotides to the 3′ terminus end of DNA. The TDT enzyme in human cells contributes to immune diversity by adding nucleotides of varying lengths between gene segments during V(D)J recombination.

V(D)J recombination

Assembles immunoglobulin and T cell receptor genes from different segments. The RAG1–RAG2 nuclease introduces DNA DSBs to produce segments that are joined by NHEJ.

Micronuclei

Pieces of DNA that reside outside of the nucleus, caused by chromosome breakage leading to accentric chromosome fragments that lack spindle attachments, or by chromosome mis-segregation during mitosis. Micronuclei are most easily detected in mature erythrocytes that lack nuclear DNA.

Ribozyme

A catalytic enzyme made entirely of RNA. Some ribozymes are nucleases and can include base-pairing regions that enable specific binding and cleavage of a target RNA molecule.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lange, S., Takata, Ki. & Wood, R. DNA polymerases and cancer. Nat Rev Cancer 11, 96–110 (2011). https://doi.org/10.1038/nrc2998

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2998

Further reading

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer