EXO1 protects BRCA1-deficient cells against toxic DNA lesions

Bert van de Kooij, Anne Schreuder, Raphael Pavani, Veronica Garzero, Sidrit Uruci, Tiemen J Wendel, Arne van Hoeck, Marta San Martin Alonso, Marieke Everts, Dana Koerse, Elsa Callen, Jasper Boom, Hailiang Mei, Edwin Cuppen, Martijn S Luijsterburg, Marcel A T M van Vugt, André Nussenzweig, Haico van Attikum*, Sylvie M Noordermeer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)659-674.e7
Number of pages24
JournalMolecular Cell
Volume84
Issue number4
DOIs
Publication statusPublished - 15-Feb-2024

Keywords

  • BRCA1
  • cancer
  • DNA double-strand break repair
  • EXO1
  • homologous recombination
  • single-strand annealing
  • synthetic lethality

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