EXO1 protects BRCA1-deficient cells against toxic DNA lesions.

Inactivating mutations in the BRCA1 and BRCA2 genes impair DNA double-strand break (DSB) repair by homologous recombination (HR), leading to chromosomal instability and cancer. Importantly, BRCA1/2 deficiency also causes therapeutically targetable vulnerabilities. Here, we identify the dependency on the end resection factor EXO1 as a key vulnerability of BRCA1-deficient cells. EXO1 deficiency generates poly(ADP-ribose)-decorated DNA lesions during S phase that associate with unresolved DSBs and genomic instability in BRCA1-deficient but not in wild-type or BRCA2-deficient cells. Our data indicate that BRCA1/EXO1 double-deficient cells accumulate DSBs due to impaired repair by single-strand annealing (SSA) on top of their HR defect. In contrast, BRCA2-deficient cells retain SSA activity in the absence of EXO1 and hence tolerate EXO1 loss. Consistent with a dependency on EXO1-mediated SSA, we find that BRCA1 -mutated tumors show elevated EXO1 expression and increased SSA-associated genomic scars compared with BRCA1-proficient tumors. Overall, our findings uncover EXO1 as a promising therapeutic target for BRCA1-deficient tumors. [Display omitted] • EXO1 is essential for the survival of BRCA1- but not BRCA2-deficient cells • EXO1 loss induces S phase PAR signaling in both BRCA1- and BRCA2-deficient cells • EXO1 loss causes toxic DNA double-strand break accumulation in BRCA1-deficient cells • The double-strand break accumulation is caused by impaired single-strand annealing van de Kooij et al. identify loss of the exonuclease EXO1 as a vulnerability of BRCA1-deficient cells. Mechanistically, cells deficient for both BRCA1 and EXO1 suffer from unrepaired DNA double-stranded breaks due to the loss of two break repair pathways, homologous recombination, and single-strand annealing. [ABSTRACT FROM AUTHOR]