Mutant huntingtin impairs Ku70-mediated DNA repair

Yasushi Enokido, Takuya Tamura, Hikaru Ito, Anup Arumughan, Akihiko Komuro, Hiroki Shiwaku, Masaki Sone, Raphaele Foulle, Hirohide Sawada, Hiroshi Ishiguro, Tetsuya Ono, Miho Murata, Ichiro Kanazawa, Nikolai Tomilin, Kazuhiko Tagawa, Erich E. Wanker, Hitoshi Okazawa

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

DNA repair defends against naturally occurring or disease-associated DNA damage during the long lifespan of neurons and is implicated in polyglutamine disease pathology. In this study, we report that mutant huntingtin (Htt) expression in neurons causes double-strand breaks (DSBs) of genomic DNA, and Htt further promotes DSBs by impairing DNA repair. We identify Ku70, a component of the DNA damage repair complex, as a mediator of the DNA repair dysfunction in mutant Htt-expressing neurons. Mutant Htt interacts with Ku70, impairs DNA-dependent protein kinase function in nonhomologous end joining, and consequently increases DSB accumulation. Expression of exogenous Ku70 rescues abnormal behavior and pathological phenotypes in the R6/2 mouse model of Huntington's disease (HD). These results collectively suggest that Ku70 is a critical regulator of DNA damage in HD pathology.

Original languageEnglish (US)
Pages (from-to)425-443
Number of pages19
JournalJournal of Cell Biology
Volume189
Issue number3
DOIs
StatePublished - May 3 2010

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