{"doi":"10.1101/2025.11.20.689563","title":"Defective Microhomology-Mediated End-joining in SMARCB1-Deficient Tumors","abstract":"ABSTRACT Rhabdoid tumors (RTs) are highly aggressive cancers driven by biallelic mutation of SMARCB1, a core subunit of the BAF (SWI/SNF) complex. We found that SMARCB1-deficient tumors have a defect in the microhomology-mediated end-joining (MMEJ) pathway, and SMARCB1 is essential for maintaining the protein level of the core MMEJ protein Polymerase Q (POLQ). Mechanistically, SMARCB1 facilitates the nuclear export of the POLQ mRNA through its interaction with the nuclear pore complex. Interestingly, loss of MMEJ in RT cells leads to a compensatory activation of, and a hyper-dependence on, the Fanconi Anemia (FA)/BRCA pathway. Knockout or inhibition of this pathway selectively kills RT cells. Notably, RBM39 degraders, novel splicing modulators, effectively inhibit the FA/BRCA pathway and kill RT cells. SMARCB1 and other cBAF/pBAF components are important for maintenance of MMEJ activity and POLQ protein level, suggesting that BAF-deficient cancers more broadly may be treated by targeted inhibition of the FA/BRCA pathway. Teaser SMARCB1-deficient tumors lose POLQ protein and MMEJ repair, forcing a hyper-dependence on the FA/BRCA pathway.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":582767,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1237788,"name":"Shuhei Asada","orcid":"0000-0001-6116-7996","position":1,"is_corresponding":false},{"id":1494750,"name":"Huy Nguyen","orcid":"0000-0002-8221-7937","position":2,"is_corresponding":false},{"id":1236405,"name":"Yuna Hirohashi","orcid":null,"position":3,"is_corresponding":false},{"id":1494751,"name":"Lifang Sun","orcid":"0000-0002-6807-3447","position":4,"is_corresponding":false},{"id":1495115,"name":"Avneesh Saravanapavan","orcid":null,"position":5,"is_corresponding":false},{"id":575620,"name":"Sirisha Mukkavalli","orcid":"0000-0002-8875-7985","position":6,"is_corresponding":false},{"id":230281,"name":"Geoffrey I. Shapiro","orcid":"0000-0002-3331-4095","position":7,"is_corresponding":false},{"id":7163,"name":"Alan D. D’Andrea","orcid":"0000-0001-6168-6294","position":8,"is_corresponding":false},{"id":1389360,"name":"Guangli Zhu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:58:59.653747Z","pmid":"41332615","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":[]}