Hoch, Nicolas C, Hanzlikova, Hana, Rulten, Stuart L, Tétreault, Martine, Komulainen, Emilia, Ju, Limei, Hornyak, Peter, Zeng, Zhihong, Gittens, William, Rey, Stephanie A, Staras, Kevin, Mancini, Grazia M S, McKinnon, Peter J, Wang, Zhao-Qi, Wagner, Justin, Yoon, Grace and Caldecott, Keith W (2016) XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature, 541 (7635). pp. 87-91. ISSN 0028-0836
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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.
Item Type: | Article |
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Schools and Departments: | School of Life Sciences > Sussex Centre for Genome Damage and Stability |
Research Centres and Groups: | Genome Damage and Stability Centre |
Subjects: | Q Science Q Science > Q Science (General) |
Depositing User: | Keith Caldecott |
Date Deposited: | 30 Jan 2017 10:25 |
Last Modified: | 29 Jun 2017 16:06 |
URI: | http://srodev.sussex.ac.uk/id/eprint/66490 |
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