Biochemistry (Moscow)

, Volume 76, Issue 1, pp 80–93 | Cite as

Eukaryotic endonuclease VIII-Like proteins: New components of the base excision DNA repair system

  • I. R. Grin
  • D. O. ZharkovEmail author


Base excision DNA repair is necessary for removal of damaged nucleobases from the genome and their replacement with normal nucleobases. Base excision repair is initiated by DNA glycosylases, the enzymes that cleave the N-glycosidic bonds of damaged deoxynucleotides. Until recently, only eight DNA glycosylases with different substrate specificity were known in human cells. In 2002, three new human DNA glycosylases (NEIL1, NEIL2, and NEIL3) were discovered, all homologous to endonuclease VIII, a bacterial protein, which also participates in DNA repair. The role of these enzymes remains mostly unknown. In this review we discuss recent data on the substrate specificity of the NEIL enzymes, their catalytic mechanism, structure, interactions with other components of DNA repair system, and possible biological role in preventing diseases associated with DNA damage.

Key words

oxidative stress DNA repair DNA glycosylases NEIL proteins 





base excision repair








formamidopyrimidine-DNA glycosylase/endonuclease VIII




endonuclease III










thymine glycol


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  1. 1.
    Korolev, V. G. (2005) Genetika, 41, 725–735.PubMedGoogle Scholar
  2. 2.
    Zharkov, D. O. (2007) Mol. Biol. (Moscow), 41, 772–786.Google Scholar
  3. 3.
    Sidorenko, V. S., and Zharkov, D. O. (2008) Mol. Biol. (Moscow), 42, 891–903.Google Scholar
  4. 4.
    Zenkov, N. K., Lankin, V. Z., and Menshchikova, E. B. (2001) Oxidative Stress: Biochemical and Pathological Aspects [in Russian], MAIK Nauka/Interperiodica, Moscow.Google Scholar
  5. 5.
    Huffman, J. L., Sundheim, O., and Tainer, J. A. (2005) Mutat. Res., 577, 55–76.PubMedGoogle Scholar
  6. 6.
    Zharkov, D. O., Shoham, G., and Grollman, A. P. (2003) DNA Repair, 2, 839–862.CrossRefPubMedGoogle Scholar
  7. 7.
    David, S. S., and Williams, S. D. (1998) Chem. Rev., 98, 1221–1261.CrossRefPubMedGoogle Scholar
  8. 8.
    Takao, M., Kanno, S.-I., Shiromoto, T., Hasegawa, R., Ide, H., Ikeda, S., Sarker, A. H., Seki, S., Xing, J. Z., Le, X. C., Weinfeld, M., Kobayashi, K., Miyazaki, J.-I., Muijtjens, M., Hoeijmakers, J. H. J., van der Horst, G., and Yasui, A. (2002) EMBO J., 21, 3486–3493.CrossRefPubMedGoogle Scholar
  9. 9.
    Hazra, T. K., Izumi, T., Boldogh, I., Imhoff, B., Kow, Y. W., Jaruga, P., Dizdaroglu, M., and Mitra, S. (2002) Proc. Natl. Acad. Sci. USA, 99, 3523–3528.CrossRefPubMedGoogle Scholar
  10. 10.
    Hazra, T. K., Kow, Y. W., Hatahet, Z., Imhoff, B., Boldogh, I., Mokkapati, S. K., Mitra, S., and Izumi, T. (2002) J. Biol. Chem., 277, 30417–30420.CrossRefPubMedGoogle Scholar
  11. 11.
    Takao, M., Kanno, S.-I., Kobayashi, K., Zhang, Q.-M., Yonei, S., van der Horst, G. T. J., and Yasui, A. (2002) J. Biol. Chem., 277, 42205–42213.CrossRefPubMedGoogle Scholar
  12. 12.
    Bandaru, V., Sunkara, S., Wallace, S. S., and Bond, J. P. (2002) DNA Repair, 1, 517–529.CrossRefPubMedGoogle Scholar
  13. 13.
    Morland, I., Rolseth, V., Luna, L., Rognes, T., Bjoras, M., and Seeberg, E. (2002) Nucleic Acids Res., 30, 4926–4936.CrossRefPubMedGoogle Scholar
  14. 14.
    Rosenquist, T. A., Zaika, E., Fernandes, A. S., Zharkov, D. O., Miller, H., and Grollman, A. P. (2003) DNA Repair, 2, 581–591.CrossRefPubMedGoogle Scholar
  15. 15.
    Zharkov, D. O., Rieger, R. A., Iden, C. R., and Grollman, A. P. (1997) J. Biol. Chem., 272, 5335–5341.CrossRefPubMedGoogle Scholar
  16. 16.
    Rieger, R. A., McTigue, M. M., Kycia, J. H., Gerchman, S. E., Grollman, A. P., and Iden, C. R. (2000) J. Am. Soc. Mass Spectrom., 11, 505–515.CrossRefPubMedGoogle Scholar
  17. 17.
    Liu, M., Bandaru, V., Bond, J. P., Jaruga, P., Zhao, X., Christov, P. P., Burrows, C. J., Rizzo, C. J., Dizdaroglu, M., and Wallace, S. S. (2010) Proc. Natl. Acad. Sci. USA, 107, 4925–4930.CrossRefPubMedGoogle Scholar
  18. 18.
    Lavrukhin, O. V., and Lloyd, R. S. (2000) Biochemistry, 39, 15266–15271.CrossRefPubMedGoogle Scholar
  19. 19.
    Burgess, S., Jaruga, P., Dodson, M. L., Dizdaroglu, M., and Lloyd, R. S. (2002) J. Biol. Chem., 277, 2938–2944.CrossRefPubMedGoogle Scholar
  20. 20.
    Das, A., Rajagopalan, L., Mathura, V. S., Rigby, S. J., Mitra, S., and Hazra, T. K. (2004) J. Biol. Chem., 279, 47132–47138.CrossRefPubMedGoogle Scholar
  21. 21.
    Zharkov, D. O., and Grollman, A. P. (2002) Free Radic. Biol. Med., 32, 1254–1263.CrossRefPubMedGoogle Scholar
  22. 22.
    Kropachev, K. Y., Zharkov, D. O., and Grollman, A. P. (2006) Biochemistry, 45, 12039–12049.CrossRefPubMedGoogle Scholar
  23. 23.
    Sidorenko, V. S., Rot, M. A., Filipenko, M. L., Nevinsky, G. A., and Zharkov, D. O. (2008) Biochemistry (Moscow), 73, 442–450.CrossRefGoogle Scholar
  24. 24.
    Guo, Y., Bandaru, V., Jaruga, P., Zhao, X., Burrows, C. J., Iwai, S., Dizdaroglu, M., Bond, J. P., and Wallace, S. S. (2010) DNA Repair, 9, 177–190.CrossRefPubMedGoogle Scholar
  25. 25.
    Michaels, M. L., Pham, L., Cruz, C., and Miller, J. H. (1991) Nucleic Acids Res., 19, 3629–3632.CrossRefPubMedGoogle Scholar
  26. 26.
    Bandaru, V., Zhao, X., Newton, M. R., Burrows, C. J., and Wallace, S. S. (2007) DNA Repair, 6, 1629–1641.CrossRefPubMedGoogle Scholar
  27. 27.
    Jaruga, P., Birincioglu, M., Rosenquist, T. A., and Dizdaroglu, M. (2004) Biochemistry, 43, 15909–15914.CrossRefPubMedGoogle Scholar
  28. 28.
    Krishnamurthy, N., Zhao, X., Burrows, C. J., and David, S. S. (2008) Biochemistry, 47, 7137–7146.CrossRefPubMedGoogle Scholar
  29. 29.
    Grin, I. R., Dianov, G. L., and Zharkov, D. O. (2010) FEBS Lett., 584, 1553–1557.CrossRefPubMedGoogle Scholar
  30. 30.
    Jaruga, P., Xiao, Y., Vartanian, V., Lloyd, R. S., and Dizdaroglu, M. (2010) Biochemistry, 49, 1053–1055.CrossRefPubMedGoogle Scholar
  31. 31.
    Wallace, S. S., Bandaru, V., Kathe, S. D., and Bond, J. P. (2003) DNA Repair, 2, 441–453.CrossRefPubMedGoogle Scholar
  32. 32.
    Hu, J., de Souza-Pinto, N. C., Haraguchi, K., Hogue, B. A., Jaruga, P., Greenberg, M. M., Dizdaroglu, M., and Bohr, V. A. (2005) J. Biol. Chem., 280, 40544–40551.CrossRefPubMedGoogle Scholar
  33. 33.
    Dou, H., Mitra, S., and Hazra, T. K. (2003) J. Biol. Chem., 278, 49679–49684.CrossRefPubMedGoogle Scholar
  34. 34.
    Zhao, X., Krishnamurthy, N., Burrows, C. J., and David, S. S. (2010) Biochemistry, 49, 1658–1666.CrossRefPubMedGoogle Scholar
  35. 35.
    Couve-Privat, S., Mace, G., Rosselli, F., and Saparbaev, M. K. (2007) Nucleic Acids Res., 35, 5672–5682.CrossRefPubMedGoogle Scholar
  36. 36.
    Couve, S., Mace-Aime, G., Rosselli, F., and Saparbaev, M. K. (2009) J. Biol. Chem., 284, 11963–11970.CrossRefPubMedGoogle Scholar
  37. 37.
    Odell, I. D., Newick, K., Heintz, N. H., Wallace, S. S., and Pederson, D. S. (2010) DNA Repair, 9, 134–143.CrossRefPubMedGoogle Scholar
  38. 38.
    Parsons, J. L., Zharkov, D. O., and Dianov, G. L. (2005) Nucleic Acids Res., 33, 4849–4856.CrossRefPubMedGoogle Scholar
  39. 39.
    Parsons, J. L., Kavli, B., Slupphaug, G., and Dianov, G. L. (2007) Biochemistry, 46, 4158–4163.CrossRefPubMedGoogle Scholar
  40. 40.
    Ali, M. M., Hazra, T. K., Hong, D., and Kow, Y. W. (2005) DNA Repair, 4, 679–686.PubMedGoogle Scholar
  41. 41.
    Grin, I. R., Khodyreva, S. N., Nevinsky, G. A., and Zharkov, D. O. (2006) FEBS Lett., 580, 4916–4922.CrossRefPubMedGoogle Scholar
  42. 42.
    Krokeide, S. Z., Bolstad, N., Laerdahl, J. K., Bjoras, M., and Luna, L. (2009) Protein Expr. Purif., 65, 160–164.CrossRefPubMedGoogle Scholar
  43. 43.
    Takao, M., Oohata, Y., Kitadokoro, K., Kobayashi, K., Iwai, S., Yasui, A., Yonei, S., and Zhang, Q.-M. (2009) Genes Cells, 14, 261–270.CrossRefPubMedGoogle Scholar
  44. 44.
    Doublie, S., Bandaru, V., Bond, J. P., and Wallace, S. S. (2004) Proc. Natl. Acad. Sci. USA, 101, 10284–10289.CrossRefPubMedGoogle Scholar
  45. 45.
    Imamura, K., Wallace, S. S., and Doublie, S. (2009) J. Biol. Chem., 284, 26174–26183.CrossRefPubMedGoogle Scholar
  46. 46.
    Jia, L., Shafirovich, V., Geacintov, N. E., and Broyde, S. (2007) Biochemistry, 46, 5305–5314.CrossRefPubMedGoogle Scholar
  47. 47.
    Mokkapati, S. K., Wiederhold, L., Hazra, T. K., and Mitra, S. (2004) Biochemistry, 43, 11596–11604.CrossRefPubMedGoogle Scholar
  48. 48.
    Sidorenko, V. S., Nevinsky, G. A., and Zharkov, D. O. (2007) DNA Repair, 6, 317–328.CrossRefPubMedGoogle Scholar
  49. 49.
    Hegde, M. L., Theriot, C. A., Das, A., Hegde, P. M., Guo, Z., Gary, R. K., Hazra, T. K., Shen, B., and Mitra, S. (2008) J. Biol. Chem., 283, 27028–27037.CrossRefPubMedGoogle Scholar
  50. 50.
    Wiederhold, L., Leppard, J. B., Kedar, P., Karimi-Busheri, F., Rasouli-Nia, A., Weinfeld, M., Tomkinson, A. E., Izumi, T., Prasad, R., Wilson, S. H., Mitra, S., and Hazra, T. K. (2004) Mol. Cell, 15, 209–220.CrossRefPubMedGoogle Scholar
  51. 51.
    Campalans, A., Marsin, S., Nakabeppu, Y., O’Connor, T. R., Boiteux, S., and Radicella, J. P. (2005) DNA Repair, 4, 826–835.CrossRefPubMedGoogle Scholar
  52. 52.
    Dou, H., Theriot, C. A., Das, A., Hegde, M. L., Matsumoto, Y., Boldogh, I., Hazra, T. K., Bhakat, K. K., and Mitra, S. (2008) J. Biol. Chem., 283, 3130–3140.CrossRefPubMedGoogle Scholar
  53. 53.
    Guan, X., Bai, H., Shi, G., Theriot, C. A., Hazra, T. K., Mitra, S., and Lu, A.-L. (2007) Nucleic Acids Res., 35, 2463–2472.CrossRefPubMedGoogle Scholar
  54. 54.
    Das, S., Chattopadhyay, R., Bhakat, K. K., Boldogh, I., Kohno, K., Prasad, R., Wilson, S. H., and Hazra, T. K. (2007) J. Biol. Chem., 282, 28474–28484.CrossRefPubMedGoogle Scholar
  55. 55.
    Muftuoglu, M., de Souza-Pinto, N. C., Dogan, A., Aamann, M., Stevnsner, T., Rybanska, I., Kirkali, G., Dizdaroglu, M., and Bohr, V. A. (2009) J. Biol. Chem., 284, 9270–9279.CrossRefPubMedGoogle Scholar
  56. 56.
    Das, A., Boldogh, I., Lee, J. W., Harrigan, J. A., Hegde, M. L., Piotrowski, J., de Souza Pinto, N., Ramos, W., Greenberg, M. M., Hazra, T. K., Mitra, S., and Bohr, V. A. (2007) J. Biol. Chem., 282, 26591–26602.CrossRefPubMedGoogle Scholar
  57. 57.
    Bhakat, K. K., Hazra, T. K., and Mitra, S. (2004) Nucleic Acids Res., 32, 3033–3039.CrossRefPubMedGoogle Scholar
  58. 58.
    Grin, I. R., Rieger, R. A., and Zharkov, D. O. (2010) Biochem. Biophys. Res. Commun., 394, 100–105.CrossRefPubMedGoogle Scholar
  59. 59.
    Savas, S., and Ozcelik, H. (2005) BMC Cancer, 5, 107.CrossRefPubMedGoogle Scholar
  60. 60.
    Hartwig, A., and Beyersmann, D. (1989) Biol. Trace Elem. Res., 21, 359–365.CrossRefPubMedGoogle Scholar
  61. 61.
    Hirano, T., Yamaguchi, Y., and Kasai, H. (1997) Toxicol. Appl. Pharmacol., 147, 9–14.CrossRefPubMedGoogle Scholar
  62. 62.
    Grin, I. R., Konorovsky, P. G., Nevinsky, G. A., and Zharkov, D. O. (2009) Biochemistry (Moscow), 74, 1253–1260.CrossRefGoogle Scholar
  63. 63.
    Hegde, M. L., Hegde, P. M., Holthauzen, L. M. F., Hazra, T. K., Rao, K. S. J., and Mitra, S. (2010) J. Biol. Chem., 285, 28812–28825.CrossRefPubMedGoogle Scholar
  64. 64.
    Englander, E. W., and Ma, H. (2006) Mech. Ageing Dev., 127, 64–69.CrossRefPubMedGoogle Scholar
  65. 65.
    Rolseth, V., Runden-Pran, E., Luna, L., McMurray, C., Bjoras, M., and Ottersen, O. P. (2008) DNA Repair, 7, 1578–1588.CrossRefPubMedGoogle Scholar
  66. 66.
    Torisu, K., Tsuchimoto, D., Ohnishi, Y., and Nakabeppu, Y. (2005) J. Biochem., 138, 763–772.CrossRefPubMedGoogle Scholar
  67. 67.
    Hildrestrand, G. A., Neurauter, C. G., Diep, D. B., Castellanos, C. G., Krauss, S., Bjoras, M., and Luna, L. (2009) BMC Neurosci., 10, 45.CrossRefPubMedGoogle Scholar
  68. 68.
    Zhou, H., Xu, M., Huang, Q., Gates, A. T., Zhang, X. D., Castle, J. C., Stec, E., Ferrer, M., Strulovici, B., Hazuda, D. J., and Espeseth, A. S. (2008) Cell Host Microbe, 4, 495–504.CrossRefPubMedGoogle Scholar
  69. 69.
    Mikkelsen, L., Bialkowski, K., Risom, L., Lohr, M., Loft, S., and Moller, P. (2009) Free Radic. Biol. Med., 47, 608–615.CrossRefPubMedGoogle Scholar
  70. 70.
    Mori, H., Ouchida, R., Hijikata, A., Kitamura, H., Ohara, O., Li, Y., Gao, X., Yasui, A., Lloyd, R. S., and Wang, J.-Y. (2009) DNA Repair, 8, 1328–1332.CrossRefPubMedGoogle Scholar
  71. 71.
    Hildrestrand, G. A., Rolseth, V., Bjoras, M., and Luna, L. (2007) DNA Repair, 6, 1425–1433.CrossRefPubMedGoogle Scholar
  72. 72.
    Conlon, K. A., Miller, H., Rosenquist, T. A., Zharkov, D. O., and Berrios, M. (2005) DNA Repair, 4, 419–431.CrossRefPubMedGoogle Scholar
  73. 73.
    Das, A., Hazra, T. K., Boldogh, I., Mitra, S., and Bhakat, K. K. (2005) J. Biol. Chem., 280, 35272–35280.CrossRefPubMedGoogle Scholar
  74. 74.
    Kinslow, C. J., El-Zein, R. A., Rondelli, C. M., Hill, C. E., Wickliffe, J. K., and Abdel-Rahman, S. Z. (2010) Mutagenesis, 25, 171–177.CrossRefPubMedGoogle Scholar
  75. 75.
    Inoue, M., Shen, G.-P., Chaudhry, M. A., Galick, H., Blaisdell, J. O., and Wallace, S. S. (2004) Radiat. Res., 161, 409–417.CrossRefPubMedGoogle Scholar
  76. 76.
    Risom, L., Lundby, C., Thomsen, J. J., Mikkelsen, L., Loft, S., Friis, G., and Moller, P. (2007) Mutat. Res., 625, 125–133.PubMedGoogle Scholar
  77. 77.
    Roy, L. M., Jaruga, P., Wood, T. G., McCullough, A. K., Dizdaroglu, M., and Lloyd, R. S. (2007) J. Biol. Chem., 282, 15790–15798.CrossRefPubMedGoogle Scholar
  78. 78.
    Forsbring, M., Vik, E. S., Dalhus, B., Karlsen, T. H., Bergquist, A., Schrumpf, E., Bjoras, M., Boberg, K. M., and Alseth, I. (2009) Carcinogenesis, 30, 1147–1154.CrossRefPubMedGoogle Scholar
  79. 79.
    Shinmura, K., Tao, H., Goto, M., Igarashi, H., Taniguchi, T., Maekawa, M., Takezaki, T., and Sugimura, H. (2004) Carcinogenesis, 25, 2311–2317.CrossRefPubMedGoogle Scholar
  80. 80.
    Broderick, P., Bagratuni, T., Vijayakrishnan, J., Lubbe, S., Chandler, I., and Houlston, R. S. (2006) BMC Cancer, 6, 243.CrossRefPubMedGoogle Scholar
  81. 81.
    Zhai, X., Zhao, H., Liu, Z., Wang, L.-E., El-Naggar, A. K., Sturgis, E. M., and Wei, Q. (2008) Clin. Cancer Res., 14, 4345–4352.CrossRefPubMedGoogle Scholar
  82. 82.
    Kinslow, C. J., El-Zein, R. A., Hill, C. E., Wickliffe, J. K., and Abdel-Rahman, S. Z. (2008) Genes Chromosomes Cancer, 47, 923–932.CrossRefPubMedGoogle Scholar
  83. 83.
    Bosch, N., Morell, M., Ponsa, I., Mercader, J. M., Armengol, L., and Estivill, X. (2009) PLoS ONE, 4, e8269.CrossRefPubMedGoogle Scholar
  84. 84.
    Zhang, H., Ma, H., Wang, Q., Chen, M., Weng, D., Wang, H., Zhou, J., Li, Y., Sun, J., Chen, Y., Liang, X., Zhao, J., Pan, K., Wang, H., and Xia, J. (2010) Oncol. Rep., 23, 445–455.CrossRefPubMedGoogle Scholar
  85. 85.
    Vartanian, V., Lowell, B., Minko, I. G., Wood, T. G., Ceci, J. D., George, S., Ballinger, S. W., Corless, C. L., McCullough, A. K., and Lloyd, R. S. (2006) Proc. Natl. Acad. Sci. USA, 103, 1864–1869.CrossRefPubMedGoogle Scholar
  86. 86.
    Chan, M. K., Ocampo-Hafalla, M. T., Vartanian, V., Jaruga, P., Kirkali, G., Koenig, K. L., Browng, S., Lloyd, R. S., Dizdaroglu, M., and Teebor, G. W. (2009) DNA Repair, 8, 786–794.CrossRefPubMedGoogle Scholar
  87. 87.
    McDaniel, A. H., Li, X., Tordoff, M. G., Bachmanov, A. A., and Reed, D. R. (2006) Mamm. Genome, 17, 1078–1092.CrossRefPubMedGoogle Scholar
  88. 88.
    Maiti, A. K., Boldogh, I., Spratt, H., Mitra, S., and Hazra, T. K. (2008) DNA Repair, 7, 1213–1220.CrossRefPubMedGoogle Scholar
  89. 89.
    Kamiya, H., Miura, K., Ishikawa, H., Inoue, H., Nishimura, S., and Ohtsuka, E. (1992) Cancer Res., 52, 3483–3485.PubMedGoogle Scholar
  90. 90.
    Xie, Y., Yang, H., Cunanan, C., Okamoto, K., Shibata, D., Pan, J., Barnes, D. E., Lindahl, T., McIlhatton, M., Fishel, R., and Miller, J. H. (2004) Cancer Res., 64, 3096–3102.CrossRefPubMedGoogle Scholar
  91. 91.
    Larkin, M. A., Blackshields, G., Brown, N. P., Chenna, R., McGettigan, P. A., McWilliam, H., Valentin, F., Wallace, I. M., Wilm, A., Lopez, R., Thompson, J. D., Gibson, T. J., and Higgins, D. G. (2007) Bioinformatics, 23, 2947–2948.CrossRefPubMedGoogle Scholar
  92. 92.
    Felsenstein, J. (1989) Cladistics, 5, 164–166.Google Scholar

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© Pleiades Publishing, Ltd. 2011

Authors and Affiliations

  1. 1.Institute of Chemical Biology and Fundamental MedicineSiberian Division of the Russian Academy of SciencesNovosibirskRussia

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