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

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Abstract

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.

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Abbreviations

AP:

apurine/apyrimidine

BER:

base excision repair

DTT:

dithiothreitol

NE:

nuclear extract

ODN:

oligodeoxyribonucleotide

oxoG:

8-oxoguanine

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Authors and Affiliations

  1. Institute of Chemical Biology and Fundamental Medicine, Siberian Division of the Russian Academy of Sciences, pr. Lavrentieva 8, 630090, Novosibirsk, Russia

    A. G. Derevyanko, A. V. Endutkin & D. O. Zharkov

  2. Novosibirsk State University, ul. Pirogova 2, 630090, Novosibirsk, Russia

    A. G. Derevyanko, A. V. Endutkin & D. O. Zharkov

  3. UMR 8126 C.N.R.S., Institut Gustave Roussy, Universite Paris-Sud XI, Villejuif Cedex, F-94805, France

    A. A. Ishchenko & M. K. Saparbaev

Authors
  1. A. G. Derevyanko
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  2. A. V. Endutkin
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  3. A. A. Ishchenko
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  4. M. K. Saparbaev
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  5. D. O. Zharkov
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Correspondence to D. O. Zharkov.

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Original Russian Text © A. G. Derevyanko, A. V. Endutkin, A. A. Ishchenko, M. K. Saparbaev, D. O. Zharkov, 2012, published in Biokhimiya, 2012, Vol. 77, No. 3, pp. 342–353.

Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM11-230, January 22, 2012.

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Derevyanko, A.G., Endutkin, A.V., Ishchenko, A.A. et al. Initiation of 8-oxoguanine base excision repair within trinucleotide tandem repeats. Biochemistry Moscow 77, 270–279 (2012). https://doi.org/10.1134/S0006297912030054

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  • DOI: https://doi.org/10.1134/S0006297912030054

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