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Nature. 2017 Jan 5;541(7635):87-91. doi: 10.1038/nature20790. Epub 2016 Dec 21.

XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.

Author information

1
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
2
CAPES Foundation, Ministry of Education of Brazil, Brasilia/DF 70040-020, Brazil.
3
Department of Human Genetics, McGill University and Genome Québec Innovation Centre, Montréal, Québec, H3A 0G4, Canada.
4
Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
5
Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
6
St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
7
Leibniz Institute for Age Research, Fritz Lipmann Institute, 1107745 Jena, Germany.
8
The Children's Hospital of Eastern Ontario Research Institute, Ottawa, K1L 8H1, Canada.
9
Division of Clinical and Metabolic Genetics, and Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, M5G 1X8, Canada.

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.

PMID:
28002403
PMCID:
PMC5218588
DOI:
10.1038/nature20790
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare that there is no conflict of interest.

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