{"doi":"10.1038/s41388-024-03264-1","title":"PRMT5-regulated splicing of DNA repair genes drives chemoresistance in breast cancer stem cells","abstract":"<jats:title>Abstract</jats:title>\n          <jats:p>Breast cancer stem cells (BCSCs) are a rare cell population that is responsible for tumour initiation, metastasis and chemoresistance. Despite this, the mechanism by which BCSCs withstand genotoxic stress is largely unknown. Here, we uncover a pivotal role for the arginine methyltransferase PRMT5 in mediating BCSC chemoresistance by modulating DNA repair efficiency. Mechanistically, we identify PRMT5 as a major regulator of DNA damage response (DDR) gene splicing in BCSCs, particularly those integral to the Fanconi Anaemia and homologous recombination pathways, with PRMT5 inhibition synergising with chemotherapy to promote BCSC apoptosis. A comparison of BCSCs and their bulk cell progeny identified some shared (<jats:italic>ATM, DDX11, EXO1, FAN1, SLX4</jats:italic>) but many unique (<jats:italic>ATR, RAD17, RAD51D, RUVBL1</jats:italic>) PRMT5-dependent alternative DDR splicing events. Surprisingly, these skipped exons and retained intron events rarely lead to substantial gene expression repression, suggesting that PRMT5 inhibition predominantly results in nuclear detention of intron-containing transcripts and the production of non-canonical isoforms with compromised protein function. Since many genes within the same DDR pathway undergo deregulated splicing, this study thus reveals additional points of vulnerability and alternative combination drug strategies that could improve the therapeutic efficacy of PRMT5 inhibitors to promote BCSC eradication.</jats:p>","journal":"Oncogene","year":2025,"id":611185,"datarank":0.44166584687496613,"base_score":2.9444389791664403,"endowment":2.9444389791664403,"self_citation_contribution":0.44166584687496613,"citation_network_contribution":0.0,"self_endowment_contribution":0.44166584687496613,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"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":687113,"name":"Kelly Chiang","orcid":null,"position":1,"is_corresponding":false},{"id":984040,"name":"Gemma L. Regan-Mochrie","orcid":"0000-0001-8012-0528","position":2,"is_corresponding":false},{"id":1572586,"name":"Soo-Youn Choi","orcid":null,"position":3,"is_corresponding":false},{"id":1572587,"name":"Ciara M. Ward","orcid":null,"position":4,"is_corresponding":false},{"id":715668,"name":"Debashish Sahay","orcid":"0000-0002-4473-6402","position":5,"is_corresponding":false},{"id":1572588,"name":"Paloma Garcia","orcid":"0000-0001-5582-8575","position":6,"is_corresponding":false},{"id":41872,"name":"Roland Arnold","orcid":null,"position":7,"is_corresponding":false},{"id":1572589,"name":"Clare C. Davies","orcid":"0000-0003-3097-1791","position":8,"is_corresponding":false},{"id":1572584,"name":"Matthew S. Gillespie","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"PRMT5-regulated splicing of DNA repair genes drives chemoresistance in breast cancer stem cells","abstract":"<jats:title>Abstract</jats:title>\n          <jats:p>Breast cancer stem cells (BCSCs) are a rare cell population that is responsible for tumour initiation, metastasis and chemoresistance. Despite this, the mechanism by which BCSCs withstand genotoxic stress is largely unknown. Here, we uncover a pivotal role for the arginine methyltransferase PRMT5 in mediating BCSC chemoresistance by modulating DNA repair efficiency. Mechanistically, we identify PRMT5 as a major regulator of DNA damage response (DDR) gene splicing in BCSCs, particularly those integral to the Fanconi Anaemia and homologous recombination pathways, with PRMT5 inhibition synergising with chemotherapy to promote BCSC apoptosis. A comparison of BCSCs and their bulk cell progeny identified some shared (<jats:italic>ATM, DDX11, EXO1, FAN1, SLX4</jats:italic>) but many unique (<jats:italic>ATR, RAD17, RAD51D, RUVBL1</jats:italic>) PRMT5-dependent alternative DDR splicing events. Surprisingly, these skipped exons and retained intron events rarely lead to substantial gene expression repression, suggesting that PRMT5 inhibition predominantly results in nuclear detention of intron-containing transcripts and the production of non-canonical isoforms with compromised protein function. Since many genes within the same DDR pathway undergo deregulated splicing, this study thus reveals additional points of vulnerability and alternative combination drug strategies that could improve the therapeutic efficacy of PRMT5 inhibitors to promote BCSC eradication.</jats:p>","is_dataset_classified":null,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39695328","pmcid":"PMC11932929","openalex_id":"https://openalex.org/W4405525121","authors":[],"funders":[{"funder_name":"Cancer Research UK","grant_id":"C52376/A25500","title":null},{"funder_name":"Breast Cancer Now","grant_id":"2023.05PR1630","title":null},{"funder_name":"Breast Cancer Now","grant_id":"2019AugPR1320","title":null}],"total_grants":3,"fwci":2.793,"citation_percentile":0.91681155,"influential_citations":0,"citation_trend":[{"year":2025,"count":12},{"year":2026,"count":5}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"https://www.nature.com/articles/s41388-024-03264-1.pdf","host_type":"journal"},{"url":"https://www.nature.com/articles/s41388-024-03264-1.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/s41388-024-03264-1","host_type":"publisher"},{"url":"https://doi.org/10.1038/s41388-024-03264-1","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39695328","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11932929","host_type":"repository"},{"url":"https://research.birmingham.ac.uk/en/publications/91e4b8c8-3924-4ceb-8b51-155b7d3cfecd","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11932929/pdf/41388_2024_Article_3264.pdf","host_type":"repository"},{"url":"https://pure-oai.bham.ac.uk/ws/files/253056753/GillespieM2024PRMTS-regulated.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11932929","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11932929?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Cancer-related gene regulation","Epigenetics and DNA Methylation","Renal and related cancers"],"mesh_terms":["Animals","Breast Neoplasms","DNA Damage","DNA Repair","Female","Humans","Protein-Arginine N-Methyltransferases","Neoplastic Stem Cells","Gene Expression Regulation, Neoplastic","Apoptosis","Alternative Splicing","Drug Resistance, Neoplasm","Cell Line, Tumor","Mice"],"keywords":["Biology","Protein arginine methyltransferase 5","DNA repair","Stem cell","DNA damage","Genetics","Cancer research","Homologous recombination","Cell biology","Gene","Methyltransferase","DNA","Methylation"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-01T16:29:00.536088Z","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":[]}