XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair.
Nat Cell Biol
; 23(12): 1287-1298, 2021 12.
Article
em En
| MEDLINE
| ID: mdl-34811483
ABSTRACT
Genetic 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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Base de dados:
MEDLINE
Assunto principal:
Transcrição Gênica
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Reparo do DNA
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Quebras de DNA de Cadeia Simples
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Proteases Específicas de Ubiquitina
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Poli(ADP-Ribose) Polimerase-1
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Proteína 1 Complementadora Cruzada de Reparo de Raio-X
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article