BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity
Research output: Contribution to journal › Journal article › peer-review
Standard
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 journal › Journal article › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
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