AI Article Synopsis
- When BRCA1 and BRCA2 genes are mutated, they can't fix DNA breaks properly, which can lead to cancer.
- Scientists found that cells with BRCA1 mutations rely on a factor called EXO1 to fix DNA damage, making EXO1 a weak spot for these cells.
- If EXO1 is missing in BRCA1-mutated cells, they struggle to repair DNA breaks, but BRCA2-mutated cells can still manage without EXO1, suggesting that targeting EXO1 could help treat BRCA1-related cancers.
Article Abstract
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.
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| http://dx.doi.org/10.1016/j.molcel.2023.12.039 | DOI Listing |
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