The study investigates the role of 53BP1 in DNA repair and genomic stability in Brca1-deficient cells. It is found that 53BP1 promotes genomic instability and tumor formation in Brca1-deficient mice by inhibiting homologous recombination (HR) repair of DNA breaks. Loss of 53BP1 reduces hypersensitivity to PARP inhibition and restores HR repair. Mechanistically, 53BP1 deletion promotes ATM-dependent processing of DNA breaks to produce single-stranded DNA competent for HR. In contrast, loss of DNA ligase 4 (Lig4) does not rescue HR defects but prevents chromatid breaks from forming chromosome rearrangements. The findings suggest that 53BP1 and Brca1 regulate the choice between HR and non-homologous end-joining (NHEJ) pathways, with implications for cancer therapy using PARP inhibitors. Specifically, ATM inhibitors could be used to resensitize Brca1-deficient tumors to PARP inhibitors.The study investigates the role of 53BP1 in DNA repair and genomic stability in Brca1-deficient cells. It is found that 53BP1 promotes genomic instability and tumor formation in Brca1-deficient mice by inhibiting homologous recombination (HR) repair of DNA breaks. Loss of 53BP1 reduces hypersensitivity to PARP inhibition and restores HR repair. Mechanistically, 53BP1 deletion promotes ATM-dependent processing of DNA breaks to produce single-stranded DNA competent for HR. In contrast, loss of DNA ligase 4 (Lig4) does not rescue HR defects but prevents chromatid breaks from forming chromosome rearrangements. The findings suggest that 53BP1 and Brca1 regulate the choice between HR and non-homologous end-joining (NHEJ) pathways, with implications for cancer therapy using PARP inhibitors. Specifically, ATM inhibitors could be used to resensitize Brca1-deficient tumors to PARP inhibitors.