Initiation of 8-oxoguanine base excision repair within trinucleotide tandem repeats |
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Authors: | A G Derevyanko A V Endutkin A A Ishchenko M K Saparbaev D O Zharkov |
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Institution: | Institute of Chemical Biology and Fundamental Medicine, Siberian Division of the Russian Academy of Sciences, Novosibirsk, 630090, Russia. |
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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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