Title |
XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia
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Published in |
Nature, December 2016
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DOI | 10.1038/nature20790 |
Pubmed ID | |
Authors |
Nicolas C. Hoch, Hana Hanzlikova, Stuart L. Rulten, Martine Tétreault, Emilia Komulainen, Limei Ju, Peter Hornyak, Zhihong Zeng, William Gittens, Stephanie A. Rey, Kevin Staras, Grazia M. S. Mancini, Peter J. McKinnon, Zhao-Qi Wang, Justin D. Wagner, Grace Yoon, Keith W. Caldecott |
Abstract |
XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease. |
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