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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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867301/
https://www.ncbi.nlm.nih.gov/pubmed/20439996
http://dx.doi.org/10.1083/jcb.200905138
Descripción
Sumario: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.