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Mutant huntingtin impairs Ku70-mediated DNA repair

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Item Type:Article
Title:Mutant huntingtin impairs Ku70-mediated DNA repair
Creators Name:Enokido, Y., Tamura, T., Ito, H., Arumughan, A., Komuro, A., Shiwaku, H., Sone, M., Foulle, R., Sawada, H., Ishiguro, H., Ono, T., Murata, M., Kanazawa, I., Tomilin, N., Tagawa, K., 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
Publisher:Rockefeller University Press
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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