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XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair
journal contribution
posted on 2023-06-10, 01:52 authored by Marek Adamowicz, Richard Hailstone, Annie Demin, Emilia KomulainenEmilia Komulainen, Hana Hanzlikova, Jan Brazina, Amit GautamAmit Gautam, Sophie Wells, Keith CaldecottKeith CaldecottGenetic defects in the repair of DNA single-strand breaks (SSBs) can result in neurological disease triggered by toxic activity of the single-strand-break sensor protein PARP1. However, the mechanism(s) by which this toxic PARP1 activity triggers cellular dysfunction are unclear. Here we show that human cells lacking XRCC1 fail to rapidly recover transcription following DNA base damage, a phenotype also observed in patient-derived fibroblasts with XRCC1 mutations and Xrcc1-/- mouse neurons. This defect is caused by excessive/aberrant PARP1 activity during DNA base excision repair, resulting from the loss of PARP1 regulation by XRCC1. We show that aberrant PARP1 activity suppresses transcriptional recovery during base excision repair by promoting excessive recruitment and activity of the ubiquitin protease USP3, which as a result reduces the level of monoubiquitinated histones important for normal transcriptional regulation. Importantly, inhibition and/or deletion of PARP1 or USP3 restores transcriptional recovery in XRCC1-/- cells, highlighting PARP1 and USP3 as possible therapeutic targets in neurological disease.
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- Published
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- Published version
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Nature Cell BiologyISSN
1465-7392Publisher
Nature ResearchExternal DOI
Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-11-26First Open Access (FOA) Date
2021-11-26First Compliant Deposit (FCD) Date
2021-11-26Usage metrics
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