Biochemistry (Moscow)

, Volume 77, Issue 3, pp 270–279 | Cite as

Initiation of 8-oxoguanine base excision repair within trinucleotide tandem repeats

  • A. G. Derevyanko
  • A. V. Endutkin
  • A. A. Ishchenko
  • M. K. Saparbaev
  • D. O. ZharkovEmail author


Trinucleotide repeat expansion provides a molecular basis for several devastating neurodegenerative diseases. In particular, expansion of a CAG run in the human HTT gene causes Huntington’s disease. One of the main reasons for triplet repeat expansion in somatic cells is base excision repair (BER), involving damaged base excision and repair DNA synthesis that may be accompanied by expansion of the repaired strand due to formation of noncanonical DNA structures. We have analyzed the kinetics of excision of a ubiquitously found oxidized purine base, 8-oxoguanine (oxoG), by DNA glycosylase OGG1 from the substrates containing a CAG run flanked by AT-rich sequences. The values of k 2 rate constant for the removal of oxoG from triplets in the middle of the run were higher than for oxoG at the flanks of the run. The value of k 3 rate constant dropped starting from the third CAG-triplet in the run and remained stable until the 3′-terminal triplet, where it decreased even more. In nuclear extracts, the profile of oxoG removal rate along the run resembled the profile of k 2 constant, suggesting that the reaction rate in the extracts is limited by base excision. The fully reconstituted BER was efficient with all substrates unless oxoG was near the 3′-flank of the run, interfering with the initiation of the repair. DNA polymerase β was able to perform a strand-displacement DNA synthesis, which may be important for CAG run expansion initiated by BER.

Key words

base excision repair trinucleotide repeat expansion CAG triplets Huntington’s disease 8-oxoguanine OGG1 





base excision repair




nuclear extract






Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Perutz, M. F., and Windle, A. H. (2001) Nature, 412, 143–144.PubMedCrossRefGoogle Scholar
  2. 2.
    Orr, H. T., and Zoghbi, H. Y. (2007) Annu. Rev. Neurosci., 30, 575–621.PubMedCrossRefGoogle Scholar
  3. 3.
    Duyao, M., Ambrose, C., Myers, R., Novelletto, A., Persichetti, F., Frontali, M., Folstein, S., Ross, C., Franz, M., Abbott, M., Gray, J., Conneally, P., Young, A., Penney, J., Hollingsworth, Z., Shoulson, I., Lazzarini, A., Falek, A., Koroshetz, W., Sax, D., Bird, E., Vonsattel, J., Bonilla, E., Alvir, J., Bickham Conde, J., Cha, J.-H., Dure, L., Gomez, F., Ramos, M., Sanchez-Ramos, J., Snodgrass, S., de Young, M., Wexler, N., Moscowitz, C., Penchaszadeh, G., MacFarlane, H., Anderson, M., Jenkins, B., Srinidhi, J., Gusella, G. B. J., and MacDonald, M. (1993) Nat. Genet., 4, 387–392.PubMedCrossRefGoogle Scholar
  4. 4.
    Walker, F. O. (2007) Lancet, 369, 218–228.PubMedCrossRefGoogle Scholar
  5. 5.
    Kennedy, L., Evans, E., Chen, C.-M., Craven, L., Detloff, P. J., Ennis, M., and Shelbourne, P. F. (2003) Hum. Mol. Genet., 12, 3359–3367.PubMedCrossRefGoogle Scholar
  6. 6.
    Kovtun, I. V., Liu, Y., Bjoras, M., Klungland, A., Wilson, S. H., and McMurray, C. T. (2007) Nature, 447, 447–452.PubMedCrossRefGoogle Scholar
  7. 7.
    Zharkov, D. O. (2008) Cell. Mol. Life Sci., 65, 1544–1565.PubMedCrossRefGoogle Scholar
  8. 8.
    Liu, Y., Prasad, R., Beard, W. A., Hou, E. W., Horton, J. K., McMurray, C. T., and Wilson, S. H. (2009) J. Biol. Chem., 284, 28352–28366.PubMedCrossRefGoogle Scholar
  9. 9.
    Goula, A.-V., Berquist, B. R., Wilson, D. M., III, Wheeler, V. C., Trottier, Y., and Merienne, K. (2009) PLoS Genet., 5, e1000749.PubMedCrossRefGoogle Scholar
  10. 10.
    Sokhansanj, B. A., Rodrigue, G. R., Fitch, J. P., and Wilson, D. M., III (2002) Nucleic Acids Res., 30, 1817–1825.PubMedCrossRefGoogle Scholar
  11. 11.
    Sambrook, J., and Russell, D. W. (2001) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.Google Scholar
  12. 12.
    Gilboa, R., Zharkov, D. O., Golan, G., Fernandes, A. S., Gerchman, S. E., Matz, E., Kycia, J. H., Grollman, A. P., and Shoham, G. (2002) J. Biol. Chem., 277, 19811–19816.PubMedCrossRefGoogle Scholar
  13. 13.
    Kuznetsov, N. A., Koval, V. V., Zharkov, D. O., Nevinsky, G. A., Douglas, K. T., and Fedorova, O. S. (2005) Nucleic Acids Res., 33, 3919–3931.PubMedCrossRefGoogle Scholar
  14. 14.
    Sidorenko, V. S., Nevinsky, G. A., and Zharkov, D. O. (2007) DNA Repair, 6, 317–328.PubMedCrossRefGoogle Scholar
  15. 15.
    Beard, W. A., and Wilson, S. H. (1995) Meth. Enzymol., 262, 98–107.PubMedCrossRefGoogle Scholar
  16. 16.
    Dignam, J. D. (1990) Meth. Enzymol., 182, 194–203.PubMedCrossRefGoogle Scholar
  17. 17.
    Stierum, R. H., Dianov, G. L., and Bohr, V. A. (1999) Nucleic Acids Res., 27, 3712–3719.PubMedCrossRefGoogle Scholar
  18. 18.
    Sinitsyna, O., Krysanova, Z., Ishchenko, A., Dikalova, A. E., Stolyarov, S., Kolosova, N., Vasunina, E., and Nevinsky, G. (2006) J. Cell. Mol. Med., 10, 206–215.PubMedCrossRefGoogle Scholar
  19. 19.
    Visnes, T., Akbari, M., Hagen, L., Slupphaug, G., and Krokan, H. E. (2008) DNA Repair, 7, 1869–1881.PubMedCrossRefGoogle Scholar
  20. 20.
    Akbari, M., and Krokan, H. E. (2012) Mutat. Res., in press.Google Scholar
  21. 21.
    Bruner, S. D., Norman, D. P. G., and Verdine, G. L. (2000) Nature, 403, 859–866.PubMedCrossRefGoogle Scholar
  22. 22.
    Kirpota, O. O., Zharkov, D. O., Buneva, V. N., and Nevinsky, G. A. (2006) Mol. Biol., 40, 952–960.CrossRefGoogle Scholar
  23. 23.
    Garber, K. B., Visootsak, J., and Warren, S. T. (2008) Eur. J. Hum. Genet., 16, 666–672.PubMedCrossRefGoogle Scholar
  24. 24.
    Hang, B., and Singer, B. (2003) Chem. Res. Toxicol., 16, 1181–1195.PubMedCrossRefGoogle Scholar
  25. 25.
    Subramanian, S., Mishra, R. K., and Singh, L. (2003) Genome Biol., 4:R13.Google Scholar
  26. 26.
    Li, Y.-C., Korol, A. B., Fahima, T., Beiles, A., and Nevo, E. (2002) Mol. Ecol., 11, 2453–2465.PubMedCrossRefGoogle Scholar
  27. 27.
    Li, Y.-C., Korol, A. B., Fahima, T., and Nevo, E. (2004) Mol. Biol. Evol., 21, 991–1007.PubMedCrossRefGoogle Scholar
  28. 28.
    Jorda, J., and Kajava, A. V. (2010) Adv. Protein Chem. Struct. Biol., 79, 59–88.PubMedCrossRefGoogle Scholar
  29. 29.
    Gonitel, R., Moffitt, H., Sathasivam, K., Woodman, B., Detloff, P. J., Faull, R. L. M., and Bates, G. P. (2008) Proc. Natl. Acad. Sci. USA, 105, 3467–3472.PubMedCrossRefGoogle Scholar
  30. 30.
    Mollersen, L., Rowe, A. D., Larsen, E., Rognes, T., and Klungland, A. (2010) PLoS Genet., 6, e1001242.PubMedCrossRefGoogle Scholar
  31. 31.
    Lee, J.-M., Zhang, J., Su, A. I., Walker, J. R., Wiltshire, T., Kang, K., Dragileva, E., Gillis, T., Lopez, E. T., Boily, M.-J., Cyr, M., Kohane, I., Gusella, J. F., MacDonald, M. E., and Wheeler, V. C. (2010) BMC Syst. Biol., 4, 29.PubMedCrossRefGoogle Scholar
  32. 32.
    Entezam, A., and Usdin, K. (2008) Nucleic Acids Res., 36, 1050–1056.PubMedCrossRefGoogle Scholar
  33. 33.
    Entezam, A., Lokanga, A. R., Le, W., Hoffman, G., and Usdin, K. (2010) Hum. Mutat., 31, 611–616.PubMedGoogle Scholar
  34. 34.
    Sharma, R., Bhatti, S., Gomez, M., Clark, R. M., Murray, C., Ashizawa, T., and Bidichandani, S. I. (2002) Hum. Mol. Genet., 11, 2175–2187.PubMedCrossRefGoogle Scholar
  35. 35.
    Clark, R. M., De Biase, I., Malykhina, A. P., Al-Mahdawi, S., Pook, M., and Bidichandani, S. I. (2007) Hum. Genet., 120, 633–640.PubMedCrossRefGoogle Scholar
  36. 36.
    Manley, K., Shirley, T. L., Flaherty, L., and Messer, A. (1999) Nat. Genet., 23, 471–473.PubMedCrossRefGoogle Scholar
  37. 37.
    Owen, B. A. L., Yang, Z., Lai, M., Gajek, M., Badger, J. D., III, Hayes, J. J., Edelmann, W., Kucherlapati, R., Wilson, T. M., and McMurray, C. T. (2005) Nat. Struct. Mol. Biol., 12, 663–670.PubMedCrossRefGoogle Scholar
  38. 38.
    Coppede, F., Migheli, F., Ceravolo, R., Bregant, E., Rocchi, A., Petrozzi, L., Unti, E., Lonigro, R., Siciliano, G., and Migliore, L. (2010) Toxicology, 278, 199–203.PubMedCrossRefGoogle Scholar
  39. 39.
    Lin, Y., and Wilson, J. H. (2007) Mol. Cell. Biol., 27, 6209–6217.PubMedCrossRefGoogle Scholar
  40. 40.
    Dickerson, R. E., Bansal, M., Calladine, C. R., Diekmann, S., Hunter, W. N., Kennard, O., von Kitzing, E., Lavery, R., Nelson, H. C. M., Olson, W. K., Saenger, W., Shakked, Z., Sklenar, H., Soumpasis, D. M., Tung, C.-S., Wang, A. H.-J., and Zhurkin, V. B. (1989) Nucleic Acids Res., 17, 1797–1803.PubMedCrossRefGoogle Scholar
  41. 41.
    Kirpota, O. O., Endutkin, A. V., Ponomarenko, M. P., Ponomarenko, P. M., Zharkov, D. O., and Nevinsky, G. A. (2011) Nucleic Acids Res., 39, 4836–4850.PubMedCrossRefGoogle Scholar
  42. 42.
    Vlahovicek, K., Kajan, L., and Pongor, S. (2003) Nucleic Acids Res., 31, 3686–3687.PubMedCrossRefGoogle Scholar
  43. 43.
    Gabrielian, A., Vlahovicek, K., and Pongor, S. (1997) FEBS Lett., 406, 69–74.PubMedCrossRefGoogle Scholar
  44. 44.
    Gromiha, M. M., Munteanu, M. G., Gabrielian, A., and Pongor, S. (1996) J. Biol. Phys., 22, 227–243.CrossRefGoogle Scholar
  45. 45.
    Banerjee, A., Yang, W., Karplus, M., and Verdine, G. L. (2005) Nature, 434, 612–618.PubMedCrossRefGoogle Scholar
  46. 46.
    Banerjee, A., and Verdine, G. L. (2006) Proc. Natl. Acad. Sci. USA, 103, 15020–15025.PubMedCrossRefGoogle Scholar
  47. 47.
    Lee, S., Radom, C. T., and Verdine, G. L. (2008) J. Am. Chem. Soc., 130, 7784–7785.PubMedCrossRefGoogle Scholar
  48. 48.
    Fromme, J. C., Bruner, S. D., Yang, W., Karplus, M., and Verdine, G. L. (2003) Nat. Struct. Biol., 10, 204–211.PubMedCrossRefGoogle Scholar
  49. 49.
    Norman, D. P. G., Bruner, S. D., and Verdine, G. L. (2001) J. Am. Chem. Soc., 123, 359–360.PubMedCrossRefGoogle Scholar
  50. 50.
    Chung, S. J., and Verdine, G. L. (2004) Chem. Biol., 11, 1643–1649.PubMedCrossRefGoogle Scholar
  51. 51.
    Bansal, M., Bhattacharyya, D., and Ravi, B. (1995) Comput. Appl. Biosci., 11, 281–287.PubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2012

Authors and Affiliations

  • A. G. Derevyanko
    • 1
    • 2
  • A. V. Endutkin
    • 1
    • 2
  • A. A. Ishchenko
    • 3
  • M. K. Saparbaev
    • 3
  • D. O. Zharkov
    • 1
    • 2
    Email author
  1. 1.Institute of Chemical Biology and Fundamental MedicineSiberian Division of the Russian Academy of SciencesNovosibirskRussia
  2. 2.Novosibirsk State UniversityNovosibirskRussia
  3. 3.UMR 8126 C.N.R.S., Institut Gustave RoussyUniversite Paris-Sud XIVillejuif CedexFrance

Personalised recommendations