Mutant huntingtin impairs Ku70-mediated DNA repair
Authors
- Y. Enokido
- T. Tamura
- H. Ito
- A. Arumughan
- A. Komuro
- H. Shiwaku
- M. Sone
- R. Foulle
- H. Sawada
- H. Ishiguro
- T. Ono
- M. Murata
- I. Kanazawa
- N. Tomilin
- K. Tagawa
- E.E. Wanker
- H. Okazawa
Journal
- Journal of Cell Biology
Citation
- J Cell Biol 189 (3): 425-443
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.