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

doi:10.1083/jcb.200905138

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

Neurology

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	425-443
Number of pages	19
Journal	Journal of Cell Biology
Volume	189
Issue number	3
DOIs	https://doi.org/10.1083/jcb.200905138
State	Published - May 3 2010

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Mutant huntingtin impairs Ku70-mediated DNA repair. / Enokido, Yasushi; Tamura, Takuya; Ito, Hikaru; Arumughan, Anup; Komuro, Akihiko; Shiwaku, Hiroki; Sone, Masaki; Foulle, Raphaele; Sawada, Hirohide; Ishiguro, Hiroshi; Ono, Tetsuya; Murata, Miho; Kanazawa, Ichiro; Tomilin, Nikolai; Tagawa, Kazuhiko; Wanker, Erich E.; Okazawa, Hitoshi.

In: Journal of Cell Biology, Vol. 189, No. 3, 03.05.2010, p. 425-443.

Research output: Contribution to journal › Article › peer-review

Enokido, Yasushi ; Tamura, Takuya ; Ito, Hikaru ; Arumughan, Anup ; Komuro, Akihiko ; Shiwaku, Hiroki ; Sone, Masaki ; Foulle, Raphaele ; Sawada, Hirohide ; Ishiguro, Hiroshi ; Ono, Tetsuya ; Murata, Miho ; Kanazawa, Ichiro ; Tomilin, Nikolai ; Tagawa, Kazuhiko ; Wanker, Erich E. ; Okazawa, Hitoshi. / Mutant huntingtin impairs Ku70-mediated DNA repair. In: Journal of Cell Biology. 2010 ; Vol. 189, No. 3. pp. 425-443.

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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.",

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AU - Sone, Masaki

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AU - Sawada, Hirohide

AU - Ishiguro, Hiroshi

AU - Ono, Tetsuya

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AU - Kanazawa, Ichiro

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