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XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia

2016; Nature Portfolio; Volume: 541; Issue: 7635 Linguagem: Inglês

10.1038/nature20790

1476-4687

Nícolas C. Hoch, Hana Hanzlíková, Stuart L. Rulten, Martine Tétreault, Emilia Komulainen, Limei Ju, P. Hornyak, Zhihong Zeng, William H. Gittens, Stéphanie Rey, Kevin Staras, Grazia M.S. Mancini, Peter J. McKinnon, Zhao‐Qi Wang, Justin D. Wagner, Grace Yoon, Keith W. Caldecott,

Cytomegalovirus and herpesvirus research

Biallelic mutations in human XRCC1 are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. This paper shows that mutated forms of human XRCC1, a scaffold protein involved in DNA single-strand break repair, are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. In cells from a patient with an XRCC1−/− mutation, rates of break repair are reduced and the single-strand break sensor protein PARP1 is hyperactivated, resulting in abnormally high levels of cellular ADP-ribose. Genetic deletion of Parp1 in Xrcc1-defective mice prevents the accumulation of excessive ADP-ribose and rescues the loss of cerebellar neurons and cerebellar ataxia. These findings point to PARP1 as a possible therapeutic target in DNA strand break repair-defective disease. 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.