DSCC1 restrains 53BP1/RIF1 signaling at DNA double-strand breaks to promote homologous recombination repair

Mammalian DNA double-strand breaks (DSBs) are repaired by homologous recombination (HR) and non-homologous end joining (NHEJ). HR occurs in the S/G2 phase, while NHEJ dominates in G1 phase. 53BP1 promotes NHEJ by recruiting RIF1 to DSBs in G1, but its inhibition during S/G2 remains unclear. Here, we identify DNA replication and sister chromatid cohesion 1 (DSCC1) as a key regulator that antagonizes 53BP1/RIF1 signaling in a cell-cycle-dependent manner. ATR-mediated phosphorylation of DSCC1 at Thr181 leads to its recruitment to DSB sites and promotes HR by facilitating DNA end resection. During S/G2, E2F1-induced DSCC1 expression is phosphorylated by cyclin-dependent kinase 2 (CDK2), enabling DSCC1 to interact with 53BP1 and restrain ataxia telangiectasia mutated (ATM)-mediated 53BP1 phosphorylation, consequently preventing RIF1 recruitment. Pathologically, DSCC1 is elevated in ovarian cancer, conferring poly (ADP-ribose) polymerase (PARP) inhibitor resistance. Thus, DSCC1 plays a crucial role in DSB repair pathway choice toward HR repair during S/G2 phase, providing a potential target to optimize PARP inhibitor therapy in BRCA1/2-proficient cancers.