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Seminar

Monday, October 23rd, 2017
11h30
Centre de Recherche - Paris - Amphith√©√Ętre Constant-Burg - 12 rue Lhomond, Paris 5e

BRCA1 and BRCA2 Tumour Suppressors Protect against Endogenous Acetaldehyde Toxicity

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. We recently investigated 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. This work therefore identifies acetaldehyde metabolism as a potential therapeutic target for the selective elimination of BRCA1/2-deficient cells and tumors.
 

Speaker(s)

Prof. Madalena TARSOUNAS
Professor of Molecular and Cell Biology, Senior Group Leader

University of Oxford, The CR-UK/MRC Oxford Institute for Radiation Oncology, Oxford UK

Invited by

Jose Arturo LONDONO-VALLEJO
Directeur de l'UMR 3244 CNRS

Institut Curie

Contact

Prof. Madalena TARSOUNAS

Professor of Molecular and Cell Biology, Senior Group Leader

University of Oxford, The CR-UK/MRC Oxford Institute for Radiation Oncology, Oxford UK

Jose Arturo LONDONO-VALLEJO

Directeur de l'UMR 3244 CNRS

Institut Curie

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