title: Mutant huntingtin impairs Ku70-mediated DNA repair.
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.
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Enokido
authors.forename: Takuya
authors.initials: T
authors.lastname: Tamura
authors.forename: Hikaru
authors.initials: H
authors.lastname: Ito
authors.forename: Anup
authors.initials: A
authors.lastname: Arumughan
authors.forename: Akihiko
authors.initials: A
authors.lastname: Komuro
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shiwaku
authors.forename: Masaki
authors.initials: M
authors.lastname: Sone
authors.forename: Raphaele
authors.initials: R
authors.lastname: Foulle
authors.forename: Hirohide
authors.initials: H
authors.lastname: Sawada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishiguro
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ono
authors.forename: Miho
authors.initials: M
authors.lastname: Murata
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kanazawa
authors.forename: Nikolai
authors.initials: N
authors.lastname: Tomilin
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tagawa
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism*; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D000072200:Ku Autoantigen; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen