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XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia

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posted on 2023-06-09, 04:58 authored by Nicolas C Hoch, Hana Hanzlikova, Stuart L Rulten, Martine Tétreault, Emilia KomulainenEmilia Komulainen, Limei Ju, Peter Hornyak, Zhihong Zeng, William Gittens, Stephanie A Rey, Kevin StarasKevin Staras, Grazia M S Mancini, Peter J McKinnon, Zhao-Qi Wang, Justin D Wagner, Care4Rare Canada Consortium, Grace Yoon, Keith CaldecottKeith Caldecott
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.

Funding

Medical research

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Nature

ISSN

0028-0836

Publisher

Nature Publishing Group

Volume

541

Page range

87-91

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-01-30

First Open Access (FOA) Date

2017-06-22

First Compliant Deposit (FCD) Date

2017-01-28

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