期刊
JOURNAL OF CELL BIOLOGY
卷 189, 期 3, 页码 425-443出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200905138
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资金
- Japan Science and Technology Agency (PRESTO
- Core Research for Evolutional Science and Technology)
- Ministry of Education, Culture, Sports, Science and Technology of Japan [16390249, 16650076, 18390254, 18650097, 17025017, 18023014, 20023011]
- Tokyo Biochemical Research Foundation
- Mitsubishi Parma Research Foundation
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [18390254, 21390265, 16390249, 17025017, 18023014, 16650076, 20023011, 18650097] Funding Source: KAKEN
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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