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Nature. 2017 Jan 5;541(7635):87-91. doi: 10.1038/nature20790. Epub 2016 Dec 21.

XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.

Author information

Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
CAPES Foundation, Ministry of Education of Brazil, Brasilia/DF 70040-020, Brazil.
Department of Human Genetics, McGill University and Genome Québec Innovation Centre, Montréal, Québec, H3A 0G4, Canada.
Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Leibniz Institute for Age Research, Fritz Lipmann Institute, 1107745 Jena, Germany.
The Children's Hospital of Eastern Ontario Research Institute, Ottawa, K1L 8H1, Canada.
Division of Clinical and Metabolic Genetics, and Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, M5G 1X8, Canada.


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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Free PMC Article

Conflict of interest statement

The authors declare that there is no conflict of interest.

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