{"doi":"10.3390/ijms241310966","title":"Selective Killing of BRCA2-Deficient Ovarian Cancer Cells via MRE11 Blockade","abstract":"<jats:p>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.</jats:p>","journal":"International Journal of Molecular Sciences","year":2023,"id":654169,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1707247,"name":"Reem Ali","orcid":null,"position":1,"is_corresponding":false},{"id":1707248,"name":"Mashael Algethami","orcid":null,"position":2,"is_corresponding":false},{"id":895365,"name":"Alison Ritchie","orcid":"0000-0002-5092-4979","position":3,"is_corresponding":false},{"id":1707249,"name":"Ahmed Shoqafi","orcid":null,"position":4,"is_corresponding":false},{"id":1707250,"name":"Shatha Alqahtani","orcid":null,"position":5,"is_corresponding":false},{"id":1707251,"name":"Katia A. Mesquita","orcid":"0000-0001-9832-5548","position":6,"is_corresponding":false},{"id":581628,"name":"Michael S. Toss","orcid":"0000-0002-9077-3984","position":7,"is_corresponding":false},{"id":1707252,"name":"Paloma Ordóñez-Morán","orcid":null,"position":8,"is_corresponding":false},{"id":1707253,"name":"Jennie N. Jeyapalan","orcid":null,"position":9,"is_corresponding":false},{"id":1707254,"name":"Lodewijk Dekker","orcid":"0000-0001-5247-3297","position":10,"is_corresponding":false},{"id":1707255,"name":"Martina Salerno","orcid":null,"position":11,"is_corresponding":false},{"id":1707256,"name":"Edgar Hartsuiker","orcid":null,"position":12,"is_corresponding":false},{"id":895369,"name":"Anna M. Grabowska","orcid":"0000-0003-1507-921X","position":13,"is_corresponding":false},{"id":320592,"name":"Emad A. Rakha","orcid":"0000-0002-5009-5525","position":14,"is_corresponding":false},{"id":679677,"name":"Nigel P. Mongan","orcid":"0000-0001-5438-1126","position":15,"is_corresponding":false},{"id":1654968,"name":"Srinivasan Madhusudan","orcid":"0000-0002-5354-5480","position":16,"is_corresponding":false},{"id":1707246,"name":"Adel Alblihy","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Selective Killing of BRCA2-Deficient Ovarian Cancer Cells via MRE11 Blockade","abstract":"<jats:p>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.</jats:p>","is_dataset_classified":null,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"37446144","pmcid":"PMC10341502","openalex_id":"https://openalex.org/W4382752503","authors":[],"funders":[{"funder_name":"Naaz-Coker Ovarian Cancer Fellowship, University of Nottingham","grant_id":"01","title":null},{"funder_name":"National Institutes of Health","grant_id":"5P41GM103311-36","title":"Resource for Biocomputing Visualization and Informatics"},{"funder_name":"Tenovus Cancer Care and Knowledge Economy Skills Scholarships (KESS 2)","grant_id":"","title":null},{"funder_name":"Naaz-Coker Ovarian Cancer Fellowship (UoN-01), University of Nottingham, UK","grant_id":"","title":null}],"total_grants":4,"fwci":0.3696,"citation_percentile":0.54041498,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":1},{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1422-0067/24/13/10966/pdf?version=1688136405","host_type":"journal"},{"url":"https://www.mdpi.com/1422-0067/24/13/10966/pdf?version=1688136405","host_type":"publisher"},{"url":"https://www.mdpi.com/1422-0067/24/13/10966/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/ijms241310966","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/37446144","host_type":"repository"},{"url":"https://dx.doi.org/10.3390/ijms241310966","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/10341502","host_type":"repository"},{"url":"https://nottingham-repository.worktribe.com/output/22726146","host_type":"repository"},{"url":"https://research.bangor.ac.uk/portal/en/researchoutputs/selective-killing-of-brca2deficient-ovarian-cancer-cells-via-mre11-blockade(54118792-0ba1-4705-a7e9-85f842785875).html","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10341502/pdf/ijms-24-10966.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC10341502","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC10341502?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.3390/ijms241310966","host_type":""}],"fields_of_study":["DNA Repair Mechanisms","CRISPR and Genetic Engineering","Genetics and Neurodevelopmental Disorders","03 medical and health sciences","0302 clinical medicine","Humans","Female","DNA-Binding Proteins","MRE11 Homologue Protein","HeLa Cells","Precision Medicine","BRCA2 Protein","DNA Repair","Ovarian Neoplasms","Cell Line, Tumor","Pyrimidinones","Thiones"],"mesh_terms":["MRE11 Homologue Protein","DNA Repair","DNA-Binding Proteins","Female","HeLa Cells","Humans","Ovarian Neoplasms","Pyrimidinones","Thiones","BRCA2 Protein","Cell Line, Tumor","Precision Medicine","Hela Cells"],"keywords":["Nuclease","Homologous recombination","Gene knockdown","Cancer research","DNA repair","Molecular biology","Biology","DNA damage","Downregulation and upregulation","Cancer cell","Cell cycle checkpoint","RAD51","Ovarian cancer","Cell biology","Apoptosis","Cell cycle","Chemistry","DNA","Cancer","Genetics","Gene","BRCA2","Synthetic Lethality","Mre11","BRCA2 Protein","Ovarian Neoplasms","MRE11 Homologue Protein","Thiones","Pyrimidinones","Article","DNA-Binding Proteins","Cell Line, Tumor","Humans","Female","Precision Medicine","HeLa Cells"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"},{"name":"hpa"},{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T04:22:15.851383Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}