Base excision repair of oxidative DNA damage coupled with removal of a CAG repeat hairpin attenuates trinucleotide repeat expansion

Meng Xu, Yanhao Lai, Justin Torner, Yanbin Zhang, Zunzhen Zhang, Yuan Liu

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Trinucleotide repeat (TNR) expansion is responsible for numerous human neurodegenerative diseases. However, the underlying mechanisms remain unclear. Recent studies have shown that DNA base excision repair (BER) can mediate TNR expansion and deletion by removing base lesions in different locations of a TNR tract, indicating that BER can promote or prevent TNR expansion in a damage location-dependent manner. In this study, we provide the first evidence that the repair of a DNA base lesion located in the loop region of a CAG repeat hairpin can remove the hairpin, attenuating repeat expansion. We found that an 8-oxoguanine located in the loop region of CAG hairpins of varying sizes was removed by OGG1 leaving an abasic site that was subsequently 50-incised by AP endonuclease 1, introducing a single-strand breakage in the hairpin loop. This converted the hairpin into a double-flap intermediate with a 50- and 30-flap that was cleaved by flap endonuclease 1 and a 30-50 endonuclease Mus81/Eme1, resulting in complete or partial removal of the CAG hairpin. This further resulted in prevention and attenuation of repeat expansion. Our results demonstrate that TNR expansion can be prevented via BER in hairpin loops that is coupled with the removal of TNR hairpins.

Original languageEnglish (US)
Pages (from-to)3675-3691
Number of pages17
JournalNucleic acids research
Volume42
Issue number6
DOIs
StatePublished - Apr 2014

ASJC Scopus subject areas

  • Genetics

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