Journal Article

XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair

Gautam, Amit, Caldecott, Keith W., Adamowicz, Marek, Demin, Annie A., Hanzlikova, Hana, Hailstone, Richard, Komulainen, Emilia, Brazina, Jan, Wells, Sophie E.

2021

Overview

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. Adamowicz et al. report that toxic PARP1 activity, induced by ataxia-associated mutations in XRCC1, impairs the recovery of global transcription during DNA base excision repair by promoting aberrant recruitment and activity of the histone ubiquitin protease USP3.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14 / 14/1 / 631/337/100/2285 / 631/337/1427/2123 / 631/337/458/582 / 631/337/572 / Animals / Ataxia / Base excision repair / Biomedical and Life Sciences / Cancer Research / Cell Biology / Cell Line, Tumor / Deoxyribonucleic acid / Development and progression / Developmental Biology / DNA / DNA - genetics / DNA binding proteins / DNA Breaks, Single-Stranded / DNA damage / DNA repair / DNA Repair - genetics / Fibroblasts / Gene regulation / Genetic aspects / Genetic research / Genetic transcription / Health aspects / Histones / Histones - metabolism / Humans / Hydrogen Peroxide - toxicity / Life Sciences / Mice / Mice, Knockout / Mutation / Nervous system diseases / Neurological diseases / Oxidative Stress - genetics / Phenotypes / Poly (ADP-Ribose) Polymerase-1 - genetics / Poly (ADP-Ribose) Polymerase-1 - metabolism / Poly(ADP-ribose) polymerase / Protease / Proteinase / Recovery / Recruitment / Repair / Stem Cells / Structure / Therapeutic targets / Toxic diseases / Transcription / Transcription, Genetic - genetics / Ubiquitin / Ubiquitin-Specific Proteases - metabolism / Ubiquitination - physiology / X-ray Repair Cross Complementing Protein 1 - genetics / X-ray Repair Cross Complementing Protein 1 - metabolism / XRCC1 protein