However, the molecular mechanism by which excessive/aberrant PARP1 activity triggers cellular dysfunction remains unclear. Intriguingly, the deletion and/or inhibition of PARP1 greatly reduces or prevents these pathologies in an Xrcc1-defective mouse model of SSB-associated neurological disease, highlighting excessive/aberrant PARP1 activity as a source of SSB-induced neuropathology 18, 19. Hereditary mutations in XRCC1 and some of these protein partners result in neurodevelopmental disorders and/or progressive neurodegeneration 2, 3. XRCC1 in turn interacts with and recruits the enzymes required for SSB repair, including DNA polymerase β 11, 12, DNA ligase III 13, polynucleotide kinase/phosphatase 14, 15 and aprataxin 16, 17. XRCC1 is a scaffold protein that is recruited to SSBs by PARP1 and/or PARP2 activity through direct interaction between poly(ADP-ribose) and the central BRCT domain in XRCC1 (refs. The extensive auto-ribosylation of PARP1 leads to disassociation of the enzyme from the SSB, enabling other DNA repair enzymes to access and repair the break 7. ADP-ribosylation accelerates SSB repair in a number of ways-for example, by modifying the structure of chromatin in the vicinity of the break and/or recruiting specific DNA repair factors such as XRCC1 (refs. Single-strand breaks are rapidly detected by poly-ADP-ribose polymerase 1 (PARP1), which following binding to the DNA break is catalytically activated and modifies itself and other proteins, such as histones, with ADP-ribose 4, 5, 6. The threat posed by SSBs is illustrated by hereditary genetic diseases in which the repair of SSBs is defective, resulting in neurological pathologies such as cerebellar ataxia, neurodevelopmental delay and seizures 2, 3. 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.ĭNA single-strand breaks (SSBs) are one of the most common types of DNA damage in cells, arising at a frequency of tens-of-thousands per cell per day 1. 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. This defect is caused by excessive/aberrant PARP1 activity during DNA base excision repair, resulting from the loss of PARP1 regulation by XRCC1. 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. However, the mechanism(s) by which this toxic PARP1 activity triggers cellular dysfunction are unclear. 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.