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EXO1 protects BRCA1-deficient cells against toxic DNA lesions.
van de Kooij, Bert; Schreuder, Anne; Pavani, Raphael; Garzero, Veronica; Uruci, Sidrit; Wendel, Tiemen J; van Hoeck, Arne; San Martin Alonso, Marta; Everts, Marieke; Koerse, Dana; Callen, Elsa; Boom, Jasper; Mei, Hailiang; Cuppen, Edwin; Luijsterburg, Martijn S; van Vugt, Marcel A T M; Nussenzweig, André; van Attikum, Haico; Noordermeer, Sylvie M.
Afiliación
  • van de Kooij B; Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands; Department of Medical Oncology, University Medical Center Groningen, Groningen 9713 GZ, the Netherlands.
  • Schreuder A; Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands; Oncode Institute, Utrecht 3521 AL, the Netherlands.
  • Pavani R; Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Garzero V; Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands; Oncode Institute, Utrecht 3521 AL, the Netherlands.
  • Uruci S; Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands.
  • Wendel TJ; Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands; Oncode Institute, Utrecht 3521 AL, the Netherlands.
  • van Hoeck A; Oncode Institute, Utrecht 3521 AL, the Netherlands; Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht 3584 CG, the Netherlands.
  • San Martin Alonso M; Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands; Oncode Institute, Utrecht 3521 AL, the Netherlands.
  • Everts M; Department of Medical Oncology, University Medical Center Groningen, Groningen 9713 GZ, the Netherlands.
  • Koerse D; Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands.
  • Callen E; Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Boom J; Sequencing Analysis Support Core, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands.
  • Mei H; Sequencing Analysis Support Core, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands.
  • Cuppen E; Oncode Institute, Utrecht 3521 AL, the Netherlands; Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht 3584 CG, the Netherlands; Hartwig Medical Foundation, Amsterdam 1098 XH, the Netherlands.
  • Luijsterburg MS; Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands.
  • van Vugt MATM; Department of Medical Oncology, University Medical Center Groningen, Groningen 9713 GZ, the Netherlands.
  • Nussenzweig A; Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • van Attikum H; Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands. Electronic address: h.van.attikum@lumc.nl.
  • Noordermeer SM; Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZC, the Netherlands; Oncode Institute, Utrecht 3521 AL, the Netherlands. Electronic address: s.m.noordermeer@lumc.nl.
Mol Cell ; 84(4): 659-674.e7, 2024 Feb 15.
Article en En | MEDLINE | ID: mdl-38266640
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína BRCA1 / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína BRCA1 / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos