XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia

  • Nature. 2017 Jan 5;541(7635):87-91. doi: 10.1038/nature20790.
Nicolas C Hoch  1  2 ,  Hana Hanzlikova  1 ,  Stuart L Rulten  1 ,  Martine Tétreault  3 ,  Emilia Komulainen  1 ,  Limei Ju  1 ,  Peter Hornyak  1 ,  Zhihong Zeng  1 ,  William Gittens  1 ,  Stephanie A Rey  4 ,  Kevin Staras  4 ,  Grazia M S Mancini  5 ,  Peter J McKinnon  6 ,  Zhao-Qi Wang  7 ,  Justin D Wagner  8 ,  Care4Rare Canada Consortium ,  Grace Yoon  9 ,  Keith W Caldecott  1
Affiliations
  • 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.
PMID: 28002403 DOI: 10.1038/nature20790
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.