XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair1,2. 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 PNKP3,4,5 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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This work was funded by MRC Programme Grants (MR/J006750/1 and MR/P010121/1) to K.W.C., a ‘Science without Borders’ postdoctoral fellowship (CAPES Foundation, Ministry of Education, Brazil, BEX9769-13-7) to N.H., and funding to G.Y. from Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, the Children’s Hospital of Eastern Ontario Foundation, and the Hospital for Sick Children. K.S. was funded by the BBSRC grant BB/K019015/1 and P.J.M. acknowledges the National Institutes of Health (NS-37956, CA-21765), the CCSG (P30 CA21765), and the American Lebanese and Syrian Associated Charities of St. Jude Children’s Research Hospital for support. We thank the patient and her family for their contribution to this study. This work was selected for study by the Care4Rare Canada (Enhanced Care for Rare Genetic Diseases in Canada) Consortium Gene Discovery Steering Committee (for committee members, see below). We thank D. Dyment for his advice and discussion. We thank S. van der Velde-Visser and J. Schuurs-Hoeijmakers for Epstein-Barr virus transformation of the patient’s and sibling’s LCLs. We also thank S. El-Khamisy and A. Ridley for preliminary analyses and assistance with the mouse work.
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Nature Reviews Molecular Cell Biology (2017)