Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps.

Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target. [Display omitted] • LIG3 is a critical suppressor of PARPi toxicity in BRCA1−/−53BP1−/− cells • Enhanced PARPi toxicity by LIG3 depletion requires BRCA1 loss but not HR deficiency • LIG3 loss induces MRE11-mediated ssDNA gaps in BRCA1−/−53BP1−/− cells exposed to PARPi • LIG3 depletion enhances efficacy of PARPi against BRCA1-deficient mouse mammary tumors Paes Dias et al. report that loss of nuclear LIG3 increases PARPi toxicity in BRCA1/53BP1 double-deficient cells by promoting the formation of MRE11-mediated post-replicative ssDNA gaps, leading to accumulation of chromosomal abnormalities. LIG3 depletion also enhances the efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]