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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Diphosphate Ribose / metabolism
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Alleles
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Animals
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Apraxias / congenital
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Apraxias / genetics
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Ataxia / genetics
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Axons / pathology
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Cerebellar Ataxia / genetics*
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Cerebellar Ataxia / pathology
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Cerebellum / metabolism
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Cerebellum / pathology
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Chromatin / metabolism
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Cogan Syndrome / genetics
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DNA Breaks, Single-Stranded
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DNA Repair / genetics
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DNA Repair Enzymes / genetics
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DNA Repair Enzymes / metabolism
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism*
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Female
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Humans
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Interneurons / metabolism
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Interneurons / pathology
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Male
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Mice
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Mutation*
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Pedigree
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Phenotype
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Poly (ADP-Ribose) Polymerase-1 / deficiency
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Poly (ADP-Ribose) Polymerase-1 / genetics
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Poly (ADP-Ribose) Polymerase-1 / metabolism*
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X-ray Repair Cross Complementing Protein 1
Substances
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Chromatin
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DNA-Binding Proteins
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X-ray Repair Cross Complementing Protein 1
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XRCC1 protein, human
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Xrcc1 protein, mouse
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Adenosine Diphosphate Ribose
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PARP1 protein, human
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Parp1 protein, mouse
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Poly (ADP-Ribose) Polymerase-1
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PNKP protein, human
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Phosphotransferases (Alcohol Group Acceptor)
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DNA Repair Enzymes
Supplementary concepts
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Apraxia, oculomotor, Cogan type