BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity

E. M. Tacconi, X. Lai, C. Folio, M. Porru, G. Zonderland, S. Badie, J. Michl, I. Sechi, M. Rogier, V. Matia Garcia, A. S. Batra, O. M. Rueda, P. Bouwman, J. Jonkers, A. Ryan, B. Reina-San-Martin, J. Hui, N. Tang, A. Bruna, A. BiroccioM. Tarsounas

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Pages (from-to)1398-1414
Number of pages17
JournalEMBO Molecular Medicine
Volume9
Issue number10
DOIs
Publication statusPublished - Oct 1 2017

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Acetaldehyde
Neoplasms
Homologous Recombination
Fanconi Anemia
Disulfiram
Poisons
DNA Damage
Fanconi Anemia Complementation Group Proteins
Fibroblasts
Recombinational DNA Repair
Aldehyde Dehydrogenase
Gene Silencing
Heterografts
Alcoholism
Hypersensitivity
Cell Death
Therapeutics
Maintenance
Genome

Keywords

  • BRCA1
  • BRCA2
  • DNA damage
  • disulfiram, acetaldehyde dehydrogenase
  • replication stress

Cite this

Tacconi, E. M., Lai, X., Folio, C., Porru, M., Zonderland, G., Badie, S., ... Tarsounas, M. (2017). BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. EMBO Molecular Medicine, 9(10), 1398-1414. https://doi.org/10.15252/emmm.201607446 [doi]

BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. / Tacconi, E. M.; Lai, X.; Folio, C.; Porru, M.; Zonderland, G.; Badie, S.; Michl, J.; Sechi, I.; Rogier, M.; Garcia, V. Matia; Batra, A. S.; Rueda, O. M.; Bouwman, P.; Jonkers, J.; Ryan, A.; Reina-San-Martin, B.; Hui, J.; Tang, N.; Bruna, A.; Biroccio, A.; Tarsounas, M.

In: EMBO Molecular Medicine, Vol. 9, No. 10, 01.10.2017, p. 1398-1414.

Research output: Contribution to journalArticle

Tacconi, EM, Lai, X, Folio, C, Porru, M, Zonderland, G, Badie, S, Michl, J, Sechi, I, Rogier, M, Garcia, VM, 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, no. 10, pp. 1398-1414. https://doi.org/10.15252/emmm.201607446 [doi]
Tacconi, E. M. ; Lai, X. ; Folio, C. ; Porru, M. ; Zonderland, G. ; Badie, S. ; Michl, J. ; Sechi, I. ; Rogier, M. ; Garcia, V. Matia ; Batra, A. S. ; Rueda, O. M. ; Bouwman, P. ; Jonkers, J. ; Ryan, A. ; Reina-San-Martin, B. ; Hui, J. ; Tang, N. ; Bruna, A. ; Biroccio, A. ; Tarsounas, M. / BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. In: EMBO Molecular Medicine. 2017 ; Vol. 9, No. 10. pp. 1398-1414.
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AU - Tacconi, E. M.

AU - Lai, X.

AU - Folio, C.

AU - Porru, M.

AU - Zonderland, G.

AU - Badie, S.

AU - Michl, J.

AU - Sechi, I.

AU - Rogier, M.

AU - Garcia, V. Matia

AU - Batra, A. S.

AU - Rueda, O. M.

AU - Bouwman, P.

AU - Jonkers, J.

AU - Ryan, A.

AU - Reina-San-Martin, B.

AU - Hui, J.

AU - Tang, N.

AU - Bruna, A.

AU - Biroccio, A.

AU - Tarsounas, M.

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