BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity

Research output: Contribution to journalJournal articlepeer-review

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BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. / Tacconi, Eliana Mc; Lai, Xianning; Folio, Cecilia; Porru, Manuela; Zonderland, Gijs; Badie, Sophie; Michl, Johanna; Sechi, Irene; Rogier, Mélanie; Matía García, Verónica; Batra, Ankita Sati; Rueda, Oscar M; Bouwman, Peter; Jonkers, Jos; Ryan, Anderson; Reina-San-Martin, Bernardo; Hui, Joannie; Tang, Nelson; Bruna, Alejandra; Biroccio, Annamaria; Tarsounas, Madalena.

In: EMBO Molecular Medicine, Vol. 9, 2017, p. 1398-1414.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Tacconi, EM, Lai, X, Folio, C, Porru, M, Zonderland, G, Badie, S, Michl, J, Sechi, I, Rogier, M, Matía García, V, Batra, AS, Rueda, OM, Bouwman, P, Jonkers, J, Ryan, A, Reina-San-Martin, B, Hui, J, Tang, N, Bruna, A, Biroccio, A & Tarsounas, M 2017, 'BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity', EMBO Molecular Medicine, vol. 9, pp. 1398-1414. https://doi.org/10.15252/emmm.201607446

APA

Tacconi, E. M., Lai, X., Folio, C., Porru, M., Zonderland, G., Badie, S., Michl, J., Sechi, I., Rogier, M., Matía García, V., Batra, A. S., Rueda, O. M., Bouwman, P., Jonkers, J., Ryan, A., Reina-San-Martin, B., Hui, J., Tang, N., Bruna, A., ... Tarsounas, M. (2017). BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. EMBO Molecular Medicine, 9, 1398-1414. https://doi.org/10.15252/emmm.201607446

Vancouver

Tacconi EM, Lai X, Folio C, Porru M, Zonderland G, Badie S et al. BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. EMBO Molecular Medicine. 2017;9:1398-1414. https://doi.org/10.15252/emmm.201607446

Author

Tacconi, Eliana Mc ; Lai, Xianning ; Folio, Cecilia ; Porru, Manuela ; Zonderland, Gijs ; Badie, Sophie ; Michl, Johanna ; Sechi, Irene ; Rogier, Mélanie ; Matía García, Verónica ; Batra, Ankita Sati ; Rueda, Oscar M ; Bouwman, Peter ; Jonkers, Jos ; Ryan, Anderson ; Reina-San-Martin, Bernardo ; Hui, Joannie ; Tang, Nelson ; Bruna, Alejandra ; Biroccio, Annamaria ; Tarsounas, Madalena. / BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. In: EMBO Molecular Medicine. 2017 ; Vol. 9. pp. 1398-1414.

Bibtex

@article{1ba90e8af83d464391800b14460868c0,
title = "BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity",
abstract = "Maintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR-compromised cells are sensitive to acetaldehyde, similarly to FANCD2-deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde dehydrogenases (ALDHs) play key roles in endogenous acetaldehyde detoxification, and their chemical inhibition leads to cellular acetaldehyde accumulation. We find that disulfiram (Antabuse), an ALDH2 inhibitor in widespread clinical use for the treatment of alcoholism, selectively eliminates BRCA1/2-deficient cells. Consistently, Aldh2 gene inactivation suppresses proliferation of HR-deficient mouse embryonic fibroblasts (MEFs) and human fibroblasts. Hypersensitivity of cells lacking BRCA2 to acetaldehyde stems from accumulation of toxic replication-associated DNA damage, leading to checkpoint activation, G2/M arrest, and cell death. Acetaldehyde-arrested replication forks require BRCA2 and FANCD2 for protection against MRE11-dependent degradation. Importantly, acetaldehyde specifically inhibits in vivo the growth of BRCA1/2-deficient tumors and ex vivo in patient-derived tumor xenograft cells (PDTCs), including those that are resistant to poly (ADP-ribose) polymerase (PARP) inhibitors. The work presented here therefore identifies acetaldehyde metabolism as a potential therapeutic target for the selective elimination of BRCA1/2-deficient cells and tumors.",
keywords = "Journal Article",
author = "Tacconi, {Eliana Mc} and Xianning Lai and Cecilia Folio and Manuela Porru and Gijs Zonderland and Sophie Badie and Johanna Michl and Irene Sechi and M{\'e}lanie Rogier and {Mat{\'i}a Garc{\'i}a}, Ver{\'o}nica and Batra, {Ankita Sati} and Rueda, {Oscar M} and Peter Bouwman and Jos Jonkers and Anderson Ryan and Bernardo Reina-San-Martin and Joannie Hui and Nelson Tang and Alejandra Bruna and Annamaria Biroccio and Madalena Tarsounas",
note = "{\textcopyright} 2017 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2017",
doi = "10.15252/emmm.201607446",
language = "English",
volume = "9",
pages = "1398--1414",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",

}

RIS

TY - JOUR

T1 - BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity

AU - Tacconi, Eliana Mc

AU - Lai, Xianning

AU - Folio, Cecilia

AU - Porru, Manuela

AU - Zonderland, Gijs

AU - Badie, Sophie

AU - Michl, Johanna

AU - Sechi, Irene

AU - Rogier, Mélanie

AU - Matía García, Verónica

AU - Batra, Ankita Sati

AU - Rueda, Oscar M

AU - Bouwman, Peter

AU - Jonkers, Jos

AU - Ryan, Anderson

AU - Reina-San-Martin, Bernardo

AU - Hui, Joannie

AU - Tang, Nelson

AU - Bruna, Alejandra

AU - Biroccio, Annamaria

AU - Tarsounas, Madalena

N1 - © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2017

Y1 - 2017

N2 - Maintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR-compromised cells are sensitive to acetaldehyde, similarly to FANCD2-deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde dehydrogenases (ALDHs) play key roles in endogenous acetaldehyde detoxification, and their chemical inhibition leads to cellular acetaldehyde accumulation. We find that disulfiram (Antabuse), an ALDH2 inhibitor in widespread clinical use for the treatment of alcoholism, selectively eliminates BRCA1/2-deficient cells. Consistently, Aldh2 gene inactivation suppresses proliferation of HR-deficient mouse embryonic fibroblasts (MEFs) and human fibroblasts. Hypersensitivity of cells lacking BRCA2 to acetaldehyde stems from accumulation of toxic replication-associated DNA damage, leading to checkpoint activation, G2/M arrest, and cell death. Acetaldehyde-arrested replication forks require BRCA2 and FANCD2 for protection against MRE11-dependent degradation. Importantly, acetaldehyde specifically inhibits in vivo the growth of BRCA1/2-deficient tumors and ex vivo in patient-derived tumor xenograft cells (PDTCs), including those that are resistant to poly (ADP-ribose) polymerase (PARP) inhibitors. The work presented here therefore identifies acetaldehyde metabolism as a potential therapeutic target for the selective elimination of BRCA1/2-deficient cells and tumors.

AB - Maintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR-compromised cells are sensitive to acetaldehyde, similarly to FANCD2-deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde dehydrogenases (ALDHs) play key roles in endogenous acetaldehyde detoxification, and their chemical inhibition leads to cellular acetaldehyde accumulation. We find that disulfiram (Antabuse), an ALDH2 inhibitor in widespread clinical use for the treatment of alcoholism, selectively eliminates BRCA1/2-deficient cells. Consistently, Aldh2 gene inactivation suppresses proliferation of HR-deficient mouse embryonic fibroblasts (MEFs) and human fibroblasts. Hypersensitivity of cells lacking BRCA2 to acetaldehyde stems from accumulation of toxic replication-associated DNA damage, leading to checkpoint activation, G2/M arrest, and cell death. Acetaldehyde-arrested replication forks require BRCA2 and FANCD2 for protection against MRE11-dependent degradation. Importantly, acetaldehyde specifically inhibits in vivo the growth of BRCA1/2-deficient tumors and ex vivo in patient-derived tumor xenograft cells (PDTCs), including those that are resistant to poly (ADP-ribose) polymerase (PARP) inhibitors. The work presented here therefore identifies acetaldehyde metabolism as a potential therapeutic target for the selective elimination of BRCA1/2-deficient cells and tumors.

KW - Journal Article

U2 - 10.15252/emmm.201607446

DO - 10.15252/emmm.201607446

M3 - Journal article

C2 - 28729482

VL - 9

SP - 1398

EP - 1414

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

ER -

ID: 182975626