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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
Selective Killing of BRCA2-Deficient Ovarian Cancer Cells via MRE11 Blockade
Adel Alblihy1, Reem Ali1, Mashael Algethami1
1Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham NG7 3RD, UK.
Abstract:
The MRE11 nuclease is essential during DNA damage recognition, homologous recombination, and replication. BRCA2 plays important roles during homologous recombination and replication. Here, we show that effecting an MRE11 blockade using a prototypical inhibitor (Mirin) induces synthetic lethality (SL) in BRCA2-deficient ovarian cancer cells, HeLa cells, and 3D spheroids compared to BRCA2-proficient controls. Increased cytotoxicity was associated with double-strand break accumulation, S-phase cell cycle arrest, and increased apoptosis. An in silico analysis revealed Mirin docking onto the active site of MRE11. While Mirin sensitises DT40 MRE11- cells to the Top1 poison SN-38, it does not sensitise nuclease-dead MRE11 cells to this compound confirming that Mirin specifically inhibits Mre11 nuclease activity. MRE11 knockdown reduced cell viability in BRCA2-deficient PEO1 cells but not in BRCA2-proficient PEO4 cells. In a Mirin-resistant model, we show the downregulation of 53BP1 and DNA repair upregulation, leading to resistance, including in in vivo xenograft models. In a clinical cohort of human ovarian tumours, low levels of BRCA2 expression with high levels of MRE11 co-expression were linked with worse progression-free survival (PFS) (p = 0.005) and overall survival (OS) (p = 0.001). We conclude that MRE11 is an attractive SL target, and the pharmaceutical development of MRE11 inhibitors for precision oncology therapeutics may be of clinical benefit.
Insights
Blocking the MRE11 nuclease with Mirin causes synthetic lethality in BRCA2-deficient ovarian cancer cells. This highlights MRE11 as a potential target for precision oncology treatments.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The MRE11 nuclease and BRCA2 protein are crucial for DNA repair processes like homologous recombination and replication.
- Deficiencies in BRCA2 are linked to various cancers, particularly ovarian cancer.
Purpose of the Study:
- To investigate the synthetic lethality (SL) induced by MRE11 inhibition in BRCA2-deficient cancer cells.
- To explore the therapeutic potential of MRE11 inhibitors in precision oncology.
Main Methods:
- Utilized Mirin, a prototypical MRE11 inhibitor, to assess its effect on BRCA2-deficient and proficient cells.
- Performed in silico analysis to confirm Mirin's binding site on MRE11.
- Investigated MRE11 knockdown effects and analyzed Mirin-resistant models.
- Examined a clinical cohort of human ovarian tumors for correlations between MRE11/BRCA2 expression and patient survival.
Main Results:
- Mirin treatment induced synthetic lethality and increased cytotoxicity in BRCA2-deficient cells, characterized by DNA double-strand breaks, S-phase arrest, and apoptosis.
- Mirin specifically inhibits MRE11 nuclease activity, as confirmed by experiments with nuclease-dead MRE11 cells.
- MRE11 knockdown reduced viability in BRCA2-deficient cells, while Mirin resistance was associated with 53BP1 downregulation and DNA repair upregulation.
- Low BRCA2 and high MRE11 expression in ovarian tumors correlated with significantly worse progression-free and overall survival.
Conclusions:
- MRE11 is a viable synthetic lethality target for precision oncology.
- MRE11 inhibitors, like Mirin, show promise as therapeutic agents for BRCA2-deficient cancers.
- Targeting MRE11 could offer clinical benefits for patients with specific DNA repair deficiencies.
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