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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity
Eliana Mc Tacconi1, Xianning Lai1, Cecilia Folio1
1Department of Oncology, Genome Stability and Tumorigenesis Group, The CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
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.
Insights
Cells with compromised homologous recombination (HR) repair are sensitive to acetaldehyde. Disulfiram, an alcohol treatment drug, selectively kills HR-deficient cancer cells by targeting acetaldehyde metabolism, offering a new therapeutic strategy.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Genome integrity relies on the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways.
- Endogenous acetaldehyde, a metabolic byproduct, causes DNA damage, especially in cells deficient in the FA protein FANCD2.
- HR-deficient cells may exhibit similar sensitivity to acetaldehyde as FANCD2-deficient cells.
Purpose of the Study:
- To investigate the sensitivity of HR-compromised cells to acetaldehyde.
- To explore the role of aldehyde dehydrogenases (ALDHs) in acetaldehyde detoxification and their impact on HR-deficient cells.
- To assess the therapeutic potential of targeting acetaldehyde metabolism in BRCA1/2-deficient cancers.
Main Methods:
- Assessing the sensitivity of BRCA1, BRCA2, and RAD51-deficient cells to acetaldehyde.
- Utilizing chemical inhibition of ALDHs, specifically disulfiram (an ALDH2 inhibitor), and gene inactivation of *Aldh2*.
- Investigating the mechanisms of DNA damage accumulation and replication fork protection in HR-deficient cells.
- Evaluating the *in vivo* and *ex vivo* efficacy of acetaldehyde-targeting agents against BRCA1/2-deficient tumors.
Main Results:
- Inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde, even with a functional FA pathway.
- Disulfiram selectively eliminates BRCA1/2-deficient cells by inhibiting ALDH2, leading to acetaldehyde accumulation.
- *Aldh2* gene inactivation suppresses the proliferation of HR-deficient fibroblasts.
- BRCA2 and FANCD2 are crucial for protecting acetaldehyde-stalled replication forks from MRE11-dependent degradation.
- Acetaldehyde inhibits the growth of BRCA1/2-deficient tumors *in vivo* and patient-derived tumor xenografts *ex vivo*, including those resistant to PARP inhibitors.
Conclusions:
- HR-compromised cells exhibit hypersensitivity to acetaldehyde due to accumulated replication-associated DNA damage.
- Targeting acetaldehyde metabolism, for example, with disulfiram, offers a selective therapeutic strategy against BRCA1/2-deficient cancers.
- This approach shows promise for treating tumors resistant to existing therapies like PARP inhibitors.
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