Abstract
SummaryMammalian 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.
Highlights
DNA base excision repair (BER) is a highly conserved pathway that is present in all organisms and required for repair of a broad range of endogenous and exogenous DNA base damage (Beard et al, 2019; Caldecott, 2020)
We show that assembly of polymerase b (POLb) and LIG3 by XRCC1 into protein complexes is required to limit poly(ADP-ribose) polymerase-1 (PARP1) engagement and activity during BER, which otherwise results in PARP1 ‘‘trapping’’ on BER intermediates in a manner reminiscent of that induced by clinical poly(ADP-ribose) polymerases (PARPs) inhibitors
XRCC1 suppresses PARP1-induced SSB accumulation and toxicity during BER To address the role of XRCC1 during BER, we first examined its functional relationship with PARP1 because the ability of XRCC1 to interact directly with poly(ADP-ribose) is critical for this role (Breslin et al, 2015)
Summary
DNA base excision repair (BER) is a highly conserved pathway that is present in all organisms and required for repair of a broad range of endogenous and exogenous DNA base damage (Beard et al, 2019; Caldecott, 2020). The canonical BER pathway involves removal of the damaged base by a DNA glycosylase, incision of the resulting abasic site by AP endonuclease (apurinic/ apyrimidinic endonuclease; APE), replacement of the missing nucleotide and removal of the terminal sugar phosphate by DNA polymerase b (POLb), and ligation of the resulting nick by DNA ligase I (LIG1) or DNA ligase III (LIG3) (Beard et al, 2019; Caldecott, 2020). PARP1 and PARP2 are sensor proteins that detect and are activated by DNA strand breaks, resulting in the posttranslational modification of themselves and other proteins with ADP-ribose (Ameet al., 1999; Benjamin and Gill, 1980; Hanzlikova et al, 2018; de Murcia and Menissier de Murcia, 1994). PARP activity can promote recruitment of other DNA repair proteins to accelerate repair of DNA strand breaks, of
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
