title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
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.
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.|CAPES Foundation, Ministry of Education of Brazil, Brasilia/DF 70040-020, Brazil.
authors.forename: Nicolas C
authors.initials: NC
authors.lastname: Hoch
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
authors.forename: Hana
authors.initials: H
authors.lastname: Hanzlikova
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Rulten
authors.affiliation: Department of Human Genetics, McGill University and Genome Québec Innovation Centre, Montréal, Québec, H3A 0G4, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Tétreault
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
authors.forename: Emilia
authors.initials: E
authors.lastname: Komulainen
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
authors.forename: Limei
authors.initials: L
authors.lastname: Ju
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Hornyak
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
authors.forename: William
authors.initials: W
authors.lastname: Gittens
authors.affiliation: Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Rey
authors.affiliation: Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Staras
authors.affiliation: Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, 1107745 Jena, Germany.
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
authors.affiliation: The Children's Hospital of Eastern Ontario Research Institute, Ottawa, K1L 8H1, Canada.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Wagner
authors.affiliation: Division of Clinical and Metabolic Genetics, and Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, M5G 1X8, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Yoon
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Caldecott
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001072:Apraxias / Q000151:congenital / Q000235:genetics; D001259:Ataxia / Q000235:genetics; D001369:Axons / Q000473:pathology; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000378:metabolism; D055952:Cogan Syndrome / Q000235:genetics; D053904:DNA Breaks, Single-Stranded; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C000619352:Xrcc1 protein, mouse; D000246:Adenosine Diphosphate Ribose; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; C530380:PNKP protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); D045643:DNA Repair Enzymes