title: Base excision repair of oxidative DNA damage coupled with removal of a CAG repeat hairpin attenuates trinucleotide repeat expansion.
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 5'-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 5'- and 3'-flap that was cleaved by flap endonuclease 1 and a 3'-5' 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.
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA, Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P. R. China and Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.forename: Yanhao
authors.initials: Y
authors.lastname: Lai
authors.forename: Justin
authors.initials: J
authors.lastname: Torner
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zunzhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism; D045585:Flap Endonucleases / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D018384:Oxidative Stress; D019680:Trinucleotide Repeat Expansion; D018911:Trinucleotide Repeats
chemical_list: C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D019951:DNA Polymerase beta; D004706:Endodeoxyribonucleases; D045585:Flap Endonucleases; D045647:DNA Glycosylases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase