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 beta 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 beta 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.

Automated summary

PARPs and XRCC1 accelerate mammalian DNA base excision repair (BER), where XRCC1 prevents excessive PARP1 engagement during BER and traps PARP1 on BER intermediates. Excessive PARP1 engagement poses a threat to genome integrity, while XRCC1 acts as an anti-trapper preventing toxic PARP1 activity. Deletion of PARP1 rescues BER and resistance to base damage in XRCC1-deficient cells.