Biochemistry (Moscow)

, Volume 75, Issue 8, pp 959–964 | Cite as

DNA polymerases and carcinogenesis

  • V. M. Krutyakov
  • T. P. KravetskayaEmail author


There are many various chromosomal and gene mutations in human cancer cells. The total mutation rate in normal human cells is 2·10−7 mutations/gene/division. From 6 to 12 carcinogenic mutations can arise by the end of the life, and these can affect the structure of ∼150 protooncogenes and genes encoding suppressors of tumor growth. However, this does not explain the tens and hundreds of thousands of mutations detectable in cancer cells. Mutation is any change of nucleotide sequence in cellular DNA. Gene mutations are mainly consequences of errors of DNA polymerases, especially of their specialized fraction (inaccurate DNA polymerases β, ζ, η, θ, ι, κ, λ, μ, σ, ν, Rev1, and terminal deoxynucleotidyl transferase, and only polymerases θ and σ manifest a slight 3′-exonuclease activity) and also consequences of a decrease in the rate of repair of these errors. Inaccurate specialized human polymerases are able to synthesize DNA opposite lesions in the DNA template, but their accuracy is especially low during synthesis on undamaged DNA. In the present review fundamental features of such polymerases are considered. DNA synthesis stops in the area of its lesion, but this block is overcome due to activities of inaccurate specialized DNA polymerases. After the lesion is bypassed, DNA synthesis is switched to accurate polymerases α, δ, ɛ, or γ. Mechanisms of direct and reverse switches of DNA polymerases as well as their modifications during carcinogenesis are discussed.

Key words

DNA polymerases and their lesions carcinogenesis mutagenesis switch of DNA polymerases 




AP sites

apurine and apyrimidine sites


corrective 3′→5′-exonucleases


proliferating cell nuclear antigen


small ubiquitin-like modifier


terminal deoxynucleotidyl transferase


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  1. 1.
    Hubscher, U., Maga, G., and Spadari, S. (2002) Annu. Rev. Biochem., 71, 133–163.CrossRefPubMedGoogle Scholar
  2. 2.
    Friedberg, E. C., Wagner, R., and Radman, M. (2002) Science, 296, 1627–1630.CrossRefPubMedGoogle Scholar
  3. 3.
    Bollum, F. D. (1978) Adv. Enzymol., 47, 347–374.PubMedGoogle Scholar
  4. 4.
    Chang, M. S. C. (1976) Science, 191, 1183–1185.CrossRefPubMedGoogle Scholar
  5. 5.
    Lawrence, C. W., and Hinkle, D. S. (1996) Cancer Surveys, 28, 21–31.PubMedGoogle Scholar
  6. 6.
    Ramadan, K., Shevelev, I. V., Maga, G., and Hubscher, U. (2002) J. Biol. Chem., 277, 18454–18458.CrossRefPubMedGoogle Scholar
  7. 7.
    Yoshida, S., Masaki, S., Nakamura, H., and Morita, T. (1981) Biochim. Biophys. Acta, 65, 324–333.Google Scholar
  8. 8.
    Kleiner, N. E., Kravetskaya, T. P., Legina, O. K., Naryzhny, S. N., and Krutyakov, V. M. (1988) Mol. Biol. (Moscow), 22, 498–505.Google Scholar
  9. 9.
    Krutyakov, V. M., Belyakova, N. V., Kravetskaya, T. P., and Naryzhny, S. N. (1985) Izv. Akad. Nauk SSSR, Ser. Biol., 4, 562–571.Google Scholar
  10. 10.
    Prasad, R., Beard, W. A., and Wilson, S. H. (1994) J. Biol. Chem., 269, 18096–18101.PubMedGoogle Scholar
  11. 11.
    Sobol, R. W., Prasad, R., Evenski, A., Baker, A., and Yang, X. P. (2000) Nature, 405, 807–810.CrossRefPubMedGoogle Scholar
  12. 12.
    Sugo, N., Aratani, Y., Nagashima, Y., Kubota, Y., and Koyama, H. (2000) EMBO J., 19, 1397–1404.CrossRefPubMedGoogle Scholar
  13. 13.
    Kunkel, T. A. (1992) BioEssays, 14, 303–308.CrossRefPubMedGoogle Scholar
  14. 14.
    Matsuda, T., Vande Berg, B. J., Bebenek, K., Osherhoff, W. P., Wilson, S. H., and Kunkel, T. A. (2003) J. Biol. Chem., 278, 25947–25951.CrossRefPubMedGoogle Scholar
  15. 15.
    Servant, L., Casaux, C., Bieth, A., Iwai, S., Hanaoka, F., and Hoffmann, J. S. (2002) J. Biol. Chem., 277, 50046–50053.CrossRefPubMedGoogle Scholar
  16. 16.
    Hubscher, U., Nasheuer, H. P., and Syvaoja, J. E. (2000) Trends Biochem. Sci., 25, 143–147.CrossRefPubMedGoogle Scholar
  17. 17.
    Hoffmann, J. S., Pillaire, M. J., Maga, G., Podust, V., Hubscher, U., and Villani, G. (1995) Proc. Natl. Acad. Sci. USA, 92, 5356–5360.CrossRefPubMedGoogle Scholar
  18. 18.
    Singh, J., Su, L., and Snow, E. T. (1996) J. Biol. Chem., 271, 28391–28398.CrossRefPubMedGoogle Scholar
  19. 19.
    Masutani, C., Kusumoto, R., and Yamada, A. (1999) Nature, 399, 700–704.CrossRefPubMedGoogle Scholar
  20. 20.
    Matsuda, T., Bebenek, K., Masutani, C., Hanaoka, F., and Kunkel, T. A. (2000) Nature, 404, 1011–1013.CrossRefPubMedGoogle Scholar
  21. 21.
    Masutani, C., Araki, M., Yamada, A., Kasumoto, R., Nogimori, T., Maekawa, T., Iwai, S., and Hanaoka, F. (1999) EMBO J., 18, 3491–3501.CrossRefPubMedGoogle Scholar
  22. 22.
    Johnson, R. E., Prakash, S., and Prakash, L. (1999) Science, 283, 1001–1004.CrossRefPubMedGoogle Scholar
  23. 23.
    Haracska, L., Prakash, S., and Prakash, L. (2000) Mol. Cell Biol., 20, 8001–8007.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhang, Y., Yuan, F., Wu, X., Wang, M., Rechcoblit, O., Taylor, J. S., Geacintov, N. E., and Wang, Z. (2000) Nucleic Acids Res., 28, 4138–4146.CrossRefPubMedGoogle Scholar
  25. 25.
    Yuan, F., Zhang, Y., Rajpal, D. K., Wu, X., Guo, D., Wang, M., Taylor, J. S., and Wang, Z. (2000) J. Biol. Chem., 275, 8233–8239.CrossRefPubMedGoogle Scholar
  26. 26.
    Kokoska, R. J., McCulloch, S. D., and Kunkel, T. A. (2003) J. Biol. Chem., 278, 50537–50545.CrossRefPubMedGoogle Scholar
  27. 27.
    Kannouche, P., Fernandez de Henestrosa, A. R., Coull, B., Vidal, A. E., Gray, C., Zicha, D., Woodhate, R., and Lehman, A. R. (2002) EMBO J., 21, 6246–6256.CrossRefPubMedGoogle Scholar
  28. 28.
    Kannouche, P., Broughton, C. C., Volker, M., Hanaoka, L. M., Millenders, L. H., and Lehman, A. R. (2001) Genes Dev., 15, 158–172.CrossRefPubMedGoogle Scholar
  29. 29.
    Ohashi, E., Ogi, T., Kusomoto, R., Iwai, S., Masutani, C., Hanaoka, F., and Ohmori, H. (2000) Genes Dev., 14, 1589–1594.PubMedGoogle Scholar
  30. 30.
    Zhang, F., Yuan, H., Xin, H., Wu, H., Rajpal, D. K., Yang, D., and Wang, Z. (2000) Nucleic Acids Res., 28, 4147–4156.CrossRefPubMedGoogle Scholar
  31. 31.
    Ohashi, E., Bebenek, K., Matsuda, T., Feaver, W. J., Gerlach, V. L., Friedberg, E. C., Ohmori, H., and Kunkel, T. A. (2000) J. Biol. Chem., 275, 39678–39684.CrossRefPubMedGoogle Scholar
  32. 32.
    Yasui, M., Suzuki, N., Miller, H., Matsuda, T., Matsui, S., and Shibutani, S. (2004) J. Mol. Biol., 344, 665–674.CrossRefPubMedGoogle Scholar
  33. 33.
    Tissier, A., McDonald, J. P., Frank, E. G., and Woodgate, R. (2000) Genes Dev., 14, 1642–1650.PubMedGoogle Scholar
  34. 34.
    Zhang, Y., Yuan, F., Wu, X., Taylor, J. S., and Wang, Z. (2001) Nucleic Acids Res., 29, 928–935.CrossRefPubMedGoogle Scholar
  35. 35.
    Tissier, A., Frank, E. G., McDonald, J. P., Iwai, S., Hanaoka, F., and Woodgate, R. (2000) EMBO J., 19, 5259–5266.CrossRefPubMedGoogle Scholar
  36. 36.
    Bebenek, K., Tissier, A., Frank, E. G., McDonald, J. P., Prasad, R., Wilson, S. H., Woodgate, R., and Kunkel, T. A. (2001) Science, 291, 2156–2159.CrossRefPubMedGoogle Scholar
  37. 37.
    Yang, J., Chen, Z., Liu, Y., Hickey, R. J., and Malkas, L. H. (2004) Cancer Res., 64, 5597–5607.CrossRefPubMedGoogle Scholar
  38. 38.
    Wabl, M., Burrows, P. D., von Gabain, A., and Steinberg, C. (1985) Proc. Natl. Acad. Sci. USA, 82, 479–482.CrossRefPubMedGoogle Scholar
  39. 39.
    Drake, J. W., Charlesworth, B., Charlesworth, D., and Crow, J. F. (1998) Genetics, 148, 1667–1686.PubMedGoogle Scholar
  40. 40.
    Krutyakov, V. M. (2004) Mol. Biol. (Moscow), 38, 823–833.Google Scholar
  41. 41.
    Fijalkowska, I. J., and Schaaper, R. M. (1996) Proc. Natl. Acad. Sci. USA, 93, 2856–2861.CrossRefPubMedGoogle Scholar
  42. 42.
    Maga, G., and Hubscher, U. (2003) J. Cell Sci., 116, 3051–3060.CrossRefPubMedGoogle Scholar
  43. 43.
    Friedberg, E. C., Lehmann, A. R., and Fuchs, P. P. (2005) Mol. Cell, 18, 499–505.CrossRefPubMedGoogle Scholar
  44. 44.
    Stelter, P., and Ulrich, H. D. (2003) Nature, 425, 188–191.CrossRefPubMedGoogle Scholar
  45. 45.
    Yeh, E. T. (2009) J. Biol. Chem., 284, 8223–8227.CrossRefPubMedGoogle Scholar
  46. 46.
    Kim, K. L., and Baek, S. H. (2006) Mol. Cells, 22, 247–253.PubMedGoogle Scholar
  47. 47.
    Kim, K. L., and Baek, S. H. (2009) Int. Rev. Cell Mol. Biol., 273, 265–311.CrossRefPubMedGoogle Scholar
  48. 48.
    Baek, S. H. (2006) Cell Cycle, 5, 1492–1495.PubMedGoogle Scholar
  49. 49.
    McCulloch, S. D., Kokoska, R. J., Chilkova, O., Welch, C. M., Johansson, E., Burgers, P. M., and Kunkel, T. A. (2004) Nucleic Acids Res., 32, 4665–4675.CrossRefPubMedGoogle Scholar
  50. 50.
    Sachidanandam, R., Weissman, D., Schmidt, S. C., Kakol, J. M., Stein, L. D., Marth, G., Sherry, S., Mullikin, J. C., Mortimore, B. J., Willey, D. L., Hunt, S. E., Cole, C. G., Coggill, P. C., Rice, C. M., Ning, Z., Rogers, J., Bentley, D. R., Kwok, P. Y., Mardis, E. R., Yeh, R. T., Schultz, B., Cook, L., Davenport, R., Dante, M., Fulton, L., Hillier, L., Waterston, R. H., McPherson, J. D., Gilman, B., Schaffner, S., van Etten, W. J., Reich, D., Higgins, J., Daly, M. J., Blumenstiel, B., Baldwin, J., Stange-Thomann, N., Zody, M. C., Linton, L., Lander, E. S., and Altshuler, D. (2001) Nature, 409, 928–933.CrossRefPubMedGoogle Scholar
  51. 51.
    Loeb, L. A. (2001) Cancer Res., 61, 3230–3239.PubMedGoogle Scholar
  52. 52.
    Bielas, J. H., and Loeb, L. A. (2005) Environ. Mol. Mutagen, 45, 206–213.CrossRefPubMedGoogle Scholar
  53. 53.
    Jonczyk, P., Fijalkowska, Y., and Ciesla, Z. (1988) Proc. Natl. Acad. Sci. USA, 85, 9124–9127.CrossRefPubMedGoogle Scholar
  54. 54.
    Ciesla, Z., Jonczyk, P., and Fijalkowska, Y. (1990) Mol. Gen. Genet., 221, 251–255.CrossRefPubMedGoogle Scholar
  55. 55.
    Hoss, M., Robins, P., Naven, T. J., Pappin, D. J., Sgouros, J., and Lingatl, T. (1999) EMBO J., 18, 3868–3875.CrossRefPubMedGoogle Scholar
  56. 56.
    Mazur, D. R., and Perrino, F. W. (1999) J. Biol. Chem., 247, 19655–19660.CrossRefGoogle Scholar
  57. 57.
    Krutyakov, V. M. (1980) in DNA Damage and Repair (Gaziev, A. I., ed.) [in Russian], Research Center of Biological Studies, Academy of Sciences of the USSR, Pushchino, pp. 95–107.Google Scholar
  58. 58.
    Krutyakov, V. M. (1985) Usp. Sovrem. Biol., 100, 191–202.Google Scholar
  59. 59.
    Wang, L., Patel, U., Gosh, L., and Banerjee, S. (1992) Cancer Res., 52, 4824–4827.PubMedGoogle Scholar
  60. 60.
    Dobashi, Y., Shuin, T., Tsuruga, H., Uemura, H., and Kubota, Y. (1994) Cancer Res., 54, 2827–2829.PubMedGoogle Scholar
  61. 61.
    Matsuzaki, J., Dobashi, Y., Miyamoto, H., Ikeda, I., Fujiami, K., Shuin, T., and Kubota, Y. (1996) Mol. Carcinogenesis, 15, 38–43.CrossRefGoogle Scholar
  62. 62.
    Canitrot, Y., Laurent, G., Astarie-Dequeker, C., Bordier, C., Cazaux, C., and Hoffmann, J. S. (2006) Anticancer Res., 26, 523–525.PubMedGoogle Scholar
  63. 63.
    Lang, T., Maitra, M., Starcevic, D., Li, S. X., and Sweasy, J. B. (2004) Proc. Natl. Acad. Sci. USA, 101, 6074–6079.CrossRefPubMedGoogle Scholar
  64. 64.
    Sweasy, J. B., Lang, T., Starcevic, D., Sun, K. W., Lai, C. C., Dimaio, D., and Dalal, S. (2005) Proc. Natl. Acad. Sci. USA, 102, 14350–14355.CrossRefPubMedGoogle Scholar
  65. 65.
    Dalal, S., Hile, S., Eckert, K. A., Sun, K. W., Starcevic, D., and Sweasy, J. B. (2005) Biochemistry, 44, 15664–15673.CrossRefPubMedGoogle Scholar
  66. 66.
    Starcevic, D., Dalal, S., and Sweasy, J. B. (2004) Cell Cycle, 3, 998–1001.PubMedGoogle Scholar
  67. 67.
    Chan, K. K., Zhang, Q. M., and Dianov, G. L. (2006) Mutagenesis, 21, 173–178.CrossRefPubMedGoogle Scholar
  68. 68.
    Goldsby, R. E., Hays, L. E., Chen, X., Olmsted, E. A., Slayton, W. B., Spangrude, G. J., and Preston, B. D. (2002) Proc. Natl. Acad. Sci. USA, 99, 15560–15565.CrossRefPubMedGoogle Scholar
  69. 69.
    Holmquist, G. P. (1998) Mutat. Res., 400, 59–68.PubMedGoogle Scholar
  70. 70.
    Buermeyer, A. B., Deschenes, S. M., Baker, S. M., and Liskaya, R. M. (1999) Ann. Rev. Genet., 33, 553–564.Google Scholar
  71. 71.
    Belyakova, N. V., Kleiner, N. E., Kravetskaya, T. P., Legina, O. K., Naryzhny, S. N., Perrino, F. W., Shevelev, I. V., and Krutyakov, V. M. (1993) Eur. J. Biochem., 217, 493–500.CrossRefPubMedGoogle Scholar
  72. 72.
    Belyakova, N. V., Kravetskaya, T. P., Legina, O. K., Ronzhina, N. L., Shevelev, I. V., and Krutyakov, V. M. (2007) Izv. Ros. Akad. Nauk, Ser. Biol., No. 5, 517–523.Google Scholar
  73. 73.
    Shevelev, I. V., Belyakova, N. V., Kravetskaya, T. P., and Krutyakov, V. M. (2002) Mol. Biol. (Moscow), 36, 1054–1061.Google Scholar
  74. 74.
    Sarasin, A. (2003) Mutat. Res., 544, 99–106.CrossRefPubMedGoogle Scholar
  75. 75.
    Nowell, P. C. (1976) Science, 194, 23–28.CrossRefPubMedGoogle Scholar

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© Pleiades Publishing, Ltd. 2010

Authors and Affiliations

  1. 1.Konstantinov Petersburg Institute of Nuclear PhysicsRussian Academy of SciencesGatchina, Leningrad RegionRussia

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