Mutant huntingtin impairs Ku70-mediated DNA repair.
J Cell Biol
; 189(3): 425-43, 2010 May 03.
Article
em En
| MEDLINE
| ID: mdl-20439996
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Antígenos Nucleares
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Proteínas de Ligação a DNA
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Reparo do DNA
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Mutação
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Proteínas do Tecido Nervoso
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Cell Biol
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Japão