Author: ["Nicolas C. Hoch","Hana Hanzlikova","Stuart L. Rulten","Martine Tétreault","Emilia Komulainen","Limei Ju","Peter Hornyak","Zhihong Zeng","William Gittens","Stephanie A. Rey","Kevin Staras","Grazia M. S. Mancini","Peter J. McKinnon","Zhao-Qi Wang"," Justin D. Wagner","Kym Boycott","Alex MacKenzie","Jacek Majewski","Michael Brudno","Dennis Bulman","David Dyment","Grace Yoon","Keith W. Caldecott"]
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Abstract
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.
Cite this article
Hoch, N., Hanzlikova, H., Rulten, S. et al. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541, 87–91 (2017). https://doi.org/10.1038/nature20790