XRCC1 prevents toxic PARP1 trapping during DNA base excision repair

Mammalian DNA base excision repair (BER) is accelerated by poly(ADP-ribose) polymerases (PARPs) and the scaffold protein XRCC1. PARPs are sensors that detect single-strand break intermediates, but the critical role of XRCC1 during BER is unknown. Here, we show that protein complexes containing DNA polymerase β and DNA ligase III that are assembled by XRCC1 prevent excessive engagement and activity of PARP1 during BER. As a result, PARP1 becomes “trapped” on BER intermediates in XRCC1-deficient cells in a manner similar to that induced by PARP inhibitors, including in patient fibroblasts from XRCC1-mutated disease. This excessive PARP1 engagement and trapping renders BER intermediates inaccessible to enzymes such as DNA polymerase β and impedes their repair. Consequently, PARP1 deletion rescues BER and resistance to base damage in XRCC1−/− cells. These data reveal excessive PARP1 engagement during BER as a threat to genome integrity and identify XRCC1 as an “anti-trapper” that prevents toxic PARP1 activity. [Display omitted] •XRCC1 prevents endogenous PARP1 trapping during DNA base excision repair•PARP1 trapping impedes base excision repair and increases sensitivity to base damage•In the absence of PARP1, XRCC1 is dispensable for DNA base excision repair Demin et al. show that the essential role of the scaffold protein XRCC1 during DNA base excision repair is to prevent toxic “trapping” of PARP1 on SSB intermediates, which otherwise block this essential repair process and lead to increased cellular sensitivity to DNA base damage.