Merged file.pdf (12.39 MB)
XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia
journal contribution
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 CaldecottXRCC1 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
NatureISSN
0028-0836Publisher
Nature Publishing GroupExternal DOI
Volume
541Page range
87-91Department 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
2017-01-30First Open Access (FOA) Date
2017-06-22First Compliant Deposit (FCD) Date
2017-01-28Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC