Mutant huntingtin impairs Ku70-mediated DNA repair.
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.
Enokido
Yasushi
Y
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Tamura
Takuya
T
Ito
Hikaru
H
Arumughan
Anup
A
Komuro
Akihiko
A
Shiwaku
Hiroki
H
Sone
Masaki
M
Foulle
Raphaele
R
Sawada
Hirohide
H
Ishiguro
Hiroshi
H
Ono
Tetsuya
T
Murata
Miho
M
Kanazawa
Ichiro
I
Tomilin
Nikolai
N
Tagawa
Kazuhiko
K
Wanker
Erich E
EE
Okazawa
Hitoshi
H
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
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