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Initiation of 8-Oxoguanine Base Excision Repair within Trinucleotide Tandem Repeats

A. G. Derevyanko1,2, A. V. Endutkin1,2, A. A. Ishchenko3, M. K. Saparbaev3, and D. O. Zharkov1,2*

1Institute of Chemical Biology and Fundamental Medicine, Siberian Division of the Russian Academy of Sciences, pr. Lavrentieva 8, 630090 Novosibirsk, Russia; fax: (383) 363-5153; E-mail: dzharkov@niboch.nsc.ru

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

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

* To whom correspondence should be addressed.

Received August 9, 2011; Revision received September 29, 2011
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 k2 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 k3 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 k2 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

DOI: 10.1134/S0006297912030054