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| Item Type: | Article |
|---|---|
| Title: | Mutant huntingtin impairs Ku70-mediated DNA repair |
| Creators Name: | Enokido, Y. and Tamura, T. and Ito, H. and Arumughan, A. and Komuro, A. and Shiwaku, H. and Sone, M. and Foulle, R. and Sawada, H. and Ishiguro, H. and Ono, T. and Murata, M. and Kanazawa, I. and Tomilin, N. and Tagawa, K. and Wanker, E.E. and Okazawa, H. |
| 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. |
| Keywords: | Nuclear Antigens, Cell Line, Double-Stranded DNA Breaks, DNA Damage, DNA Repair, DNA-Binding Proteins, Hela Cells, Huntington Disease, Mutation, Nerve Tissue Proteins, Neurons, Animals, Mice, Rats |
| Source: | Journal of Cell Biology |
| ISSN: | 0021-9525 |
| Publisher: | Rockefeller University Press |
| Volume: | 189 |
| Number: | 3 |
| Page Range: | 425-443 |
| Date: | 3 May 2010 |
| Official Publication: | https://doi.org/10.1083/jcb.200905138 |
| PubMed: | View item in PubMed |
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