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

doi:10.1016/j.molcel.2023.12.039

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 journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	659-674.e7
Journal	Molecular Cell
Volume	84
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2023.12.039
Publication status	Published - 15 Feb 2024

Keywords

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

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PIIS1097276523010857Final published version, 2.91 MBLicence: CC BY-NC-ND

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van de Kooij, B., Schreuder, A., Pavani, R., Garzero, V., Uruci, S., Wendel, T. J., van Hoeck, A., San Martin Alonso, M., Everts, M., Koerse, D., Callen, E., Boom, J., Mei, H., Cuppen, E., Luijsterburg, M. S., van Vugt, M. A. T. M., Nussenzweig, A., van Attikum, H., & Noordermeer, S. M. (2024). EXO1 protects BRCA1-deficient cells against toxic DNA lesions. Molecular Cell, 84(4), 659-674.e7. https://doi.org/10.1016/j.molcel.2023.12.039

@article{c8566623f4de48b1b64455ff0be65285,

title = "EXO1 protects BRCA1-deficient cells against toxic DNA lesions",

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.",

keywords = "BRCA1, cancer, DNA double-strand break repair, EXO1, homologous recombination, single-strand annealing, synthetic lethality",

author = "{van de Kooij}, Bert and Anne Schreuder and Raphael Pavani and Veronica Garzero and Sidrit Uruci and Wendel, {Tiemen J.} and {van Hoeck}, Arne and {San Martin Alonso}, Marta and Marieke Everts and Dana Koerse and Elsa Callen and Jasper Boom and Hailiang Mei and Edwin Cuppen and Luijsterburg, {Martijn S.} and {van Vugt}, {Marcel A.T.M.} and Andr{\'e} Nussenzweig and {van Attikum}, Haico and Noordermeer, {Sylvie M.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2024",

month = feb,

day = "15",

doi = "10.1016/j.molcel.2023.12.039",

language = "English",

volume = "84",

pages = "659--674.e7",

journal = "Molecular Cell",

issn = "1097-2765",

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van de Kooij, B, Schreuder, A, Pavani, R, Garzero, V, Uruci, S, Wendel, TJ, van Hoeck, A, San Martin Alonso, M, Everts, M, Koerse, D, Callen, E, Boom, J, Mei, H, Cuppen, E, Luijsterburg, MS, van Vugt, MATM, Nussenzweig, A, van Attikum, H & Noordermeer, SM 2024, 'EXO1 protects BRCA1-deficient cells against toxic DNA lesions', Molecular Cell, vol. 84, no. 4, pp. 659-674.e7. https://doi.org/10.1016/j.molcel.2023.12.039

TY - JOUR

T1 - EXO1 protects BRCA1-deficient cells against toxic DNA lesions

AU - van de Kooij, Bert

AU - Schreuder, Anne

AU - Pavani, Raphael

AU - Garzero, Veronica

AU - Uruci, Sidrit

AU - Wendel, Tiemen J.

AU - van Hoeck, Arne

AU - San Martin Alonso, Marta

AU - Everts, Marieke

AU - Koerse, Dana

AU - Callen, Elsa

AU - Boom, Jasper

AU - Mei, Hailiang

AU - Cuppen, Edwin

AU - Luijsterburg, Martijn S.

AU - van Vugt, Marcel A.T.M.

AU - Nussenzweig, André

AU - van Attikum, Haico

AU - Noordermeer, Sylvie M.

PY - 2024/2/15

Y1 - 2024/2/15

N2 - 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.

AB - 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.

KW - BRCA1

KW - cancer

KW - DNA double-strand break repair

KW - EXO1

KW - homologous recombination

KW - single-strand annealing

KW - synthetic lethality

UR - http://www.scopus.com/inward/record.url?scp=85184765240&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2023.12.039

DO - 10.1016/j.molcel.2023.12.039

M3 - Article

C2 - 38266640

AN - SCOPUS:85184765240

SN - 1097-2765

VL - 84

SP - 659-674.e7

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

EXO1 protects BRCA1-deficient cells against toxic DNA lesions

Abstract

Keywords

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