XRCC1 Mutation is Associated with PARP1 Hyperactivation and Cerebellar Ataxia

XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair(1,2). Here, we show that biallelic mutations in human XRCC1 are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. XRCC1-mutant patient cells exhibit not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation; a phenotype recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP(3-5) and implicating 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.