XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia
Open accessAbstract
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.
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High levels of nuclear DNA damage lead to prolonged PARP1 activation, which consumes large amounts of NAD+.
“High levels of nuclear DNA damage, e.g. in cells from aged organisms or DNA repair mutants, lead to prolonged activation of PARP1, a DNA break sensor that upon activation consumes large amounts of NAD+60.”
From The central role of DNA damage in the ageing process (2021) · cites this paper as [60]
The majority of DNA damage disorders typically present in early childhood, with the exception of AOA5.
“With the exception of AOA5, which seems to have manifested exclusively in adults so far (Hoch et al, 2017: 1; O’Connor et al, 2018: 1), the majority of DNA damage disorders typically present in early childhood.”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Hoch et al, 2017: 1
Mutations in XRCC1 cause Ataxia with Oculomotor apraxia Type 5 (AOA5).
“Defective XRCC1 manifests in individuals as Ataxia with Oculomotor apraxia Type 5 (AOA5), another slow‐progressing neurodegenerative disease.”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Hoch et al, 2017
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- Authors
- Care4Rare Canada Consortium, Hoch, N. C., Hanzlikova, H., Rulten, S. L., Tétreault, M., Komulainen, E., Ju, L., Hornyak, P., Zeng, Z., Gittens, W., Rey, S. A., Staras, K., Mancini, G. M. S., McKinnon, P. J., Wang, Z.-Q., Wagner, J. D., Yoon, G., & Caldecott, K. W.
- Affiliations
- University of Sussex (GB)
- McGill University and Génome Québec Innovation Centre (CA)
- Erasmus MC (NL)
- St. Jude Children's Research Hospital (US)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Children's Hospital of Eastern Ontario (CA)
- University of Toronto (CA)
- Corresponding author
- Yoon, Grace
- Caldecott, Keith W.
- ORCID
- Venue
- Nature
- Published
- 2016-12-21
- Volume
- 541
- Issue
- 7635
- Pages
- 87-91
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5218588
- OpenAlex
- W2563186352
- Cited by
- 269
- References
- 26
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 23 · 2023: 17 · 2022: 33 · 2021: 35 · 2020: 36 · 2019: 30 · 2018: 32 · 2017: 22 · 2016: 1
- FWCI
- 14.73
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Cancer Research UK (16771)
- Medical Research Council (MR/J006750/1, MR/P010121/1)
- Biotechnology and Biological Sciences Research Council (BB/K019015/1)
- National Cancer Institute (P01CA096832, P30CA021765)
- National Institute of Neurological Disorders and Stroke (R56NS037956, R01NS037956)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- XRCC1, PARP1, cerebellar ataxia, ocular motor apraxia, axonal neuropathy, DNA single-strand break repair, ADP-ribosylation, ADP-ribose, PNKP, therapeutic target
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, X-ray Repair Cross Complementing Protein 1, Adenosine Diphosphate Ribose, Alleles, Animals, Apraxias, Ataxia, Axons, Cerebellar Ataxia, Cerebellum, Chromatin, DNA Repair, DNA-Binding Proteins, Female, Humans, Interneurons, Male, Mutation, Pedigree, Phenotype, Phosphotransferases (Alcohol Group Acceptor), DNA Repair Enzymes, Mice, DNA Breaks, Single-Stranded, Cogan Syndrome
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