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.

• MeSH
• DNA genetika   MeSH
• genetická transkripce genetika   MeSH
• histony metabolismus   MeSH
• jednořetězcové zlomy DNA * MeSH
• lidé MeSH
• myši knockoutované MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• oprava DNA genetika   MeSH
• oxidační stres genetika   MeSH
• peroxid vodíku toxicita   MeSH
• poly(ADP-ribosa)polymerasa 1 genetika   metabolismus   MeSH
• protein XRCC1 genetika   metabolismus   MeSH
• specifické proteázy ubikvitinu metabolismus   MeSH
• ubikvitinace fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• histony MeSH
• PARP1 protein, human MeSH Prohlížeč
• peroxid vodíku MeSH
• poly(ADP-ribosa)polymerasa 1 MeSH
• protein XRCC1 MeSH
• specifické proteázy ubikvitinu MeSH
• USP3 protein, human MeSH Prohlížeč
• XRCC1 protein, human MeSH Prohlížeč