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Mutant huntingtin impairs Ku70-mediated DNA repair

Year: 2010
Type: article
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.
DOI: 10.1083/jcb.200905138
Authors: 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
Institutions: Tokyo Medical and Dental University, Max Delbrück Center, Kobe Tokiwa University, Carna Biosciences (Japan), Tohoku University, National Center of Neurology and Psychiatry, Institute of Cytology, Japan Science and Technology Agency
Language: English
Open Access status: bronze
OpenAlex ID: W2136367337
FWCI: 3.042
Cites: 109
Cited by: 141
Related to: 10