Mammalian DNA base excision repair (BER) is an essential pathway comprised of damaged base excision by a DNA glycosylase, incision by AP endonuclease-1 (APE1), end processing and gap filling by DNA polymerase β (POLβ), and DNA ligation by DNA ligase I (LIG1) or DNA ligase III (LIG3). In mammals, BER additionally employs PARP1 and/or PARP2 and the scaffold protein XRCC1 to accelerate and coordinate the overall process. Whereas PARP1 and PARP2 are sensor proteins that detect unrepaired DNA single-strand breaks, the essential role of XRCC1 during BER is unknown. Here, we have identified this role. We show that the DNA repair protein complexes that are assembled by XRCC1 compete with and prevent excessive PARP1 engagement during BER, which otherwise leads to PARP1 ‘trapping’ on BER intermediates in a manner reminiscent of that induced by clinical PARP inhibitors. We demonstrate that this elevated engagement and trapping of PARP1 collectively renders BER intermediates inaccessible to POLβ and impedes their repair. Consequently, PARP1 deletion rescues both the accessibility and repair of BER intermediates in XRCC1-/- cells, and also their cellular resistance to DNA base damage. These data demonstrate that PARP1 trapping is an endogenous threat to genome integrity, and identify XRCC1 as an “anti-trapper” that prevents the toxic binding of PARP1 to BER intermediates to ensure their efficient repair.
