XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia

Article

关键词: STRAND BREAK REPAIR;    BASE EXCISION-REPAIR;    POLY(ADP-RIBOSE) POLYMERASE;    SPINOCEREBELLAR ATAXIA;    DNA;    CELLS;    GENE;    REPLICATION;    DISEASE;    RATES;   

DOI  :  10.1038/nature20790

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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