Journal
NATURE
Volume 541, Issue 7635, Pages 87-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature20790
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Funding
- MRC [MR/J006750/1, MR/P010121/1]
- CAPES Foundation, Ministry of Education, Brazil [BEX9769-13-7]
- Genome Canada
- Canadian Institutes of Health Research
- Ontario Genomics Institute
- Ontario Research Fund
- Genome Quebec
- Children's Hospital of Eastern Ontario Foundation
- Hospital for Sick Children
- BBSRC [BB/K019015/1]
- National Institutes of Health [NS-37956, CA-21765]
- CCSG [P30 CA21765]
- American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital
- BBSRC [BB/K019015/1] Funding Source: UKRI
- MRC [MR/P010121/1, MR/J006750/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/K019015/1] Funding Source: researchfish
- Cancer Research UK [16771] Funding Source: researchfish
- Medical Research Council [MR/P010121/1, MR/J006750/1] Funding Source: researchfish
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XRCC1 is a molecular scaffold protein that assembles multiprotein complexes involved in DNA single-strand break repair(1,2). 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 PNKP3-5 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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