{"doi":"10.1101/2025.10.15.682667","title":"Human Dicer1 hotspot mutation induces both loss and gain of miRNA function","abstract":"Abstract The core miRNA biogenesis enzyme Dicer1 sustains recurrent mutations in cancer that compromise its RNase IIIb domain, which cleaves 5p arms of pre-miRNA hairpins. However, the lack of knockin models has limited fuller understanding. Here, we generated Dicer1-KO and Dicer1-S1344L (homozygous and hemizygous) human ESCs; the latter is a non-catalytic mutation in RNase IIIa that impairs RNase IIIb activity. Dicer1 knockouts lack canonical miRNAs, while S1344L induces two trends: ablation of miRNA-5p strands, and selective changes in miRNA-3p strands. Curiously, we recognized directional upregulation of miRNA-3p passenger strands, indicating a broad strand switch. We used multiple in vitro assays to show 3p arm-nicked pre-miRNAs preferentially load miRNA-3p species into Argonaute, compared to corresponding duplexes. Moreover, activity assays, RNA-seq data, and Argonaute-mRNA profiling, confirm that these confer increased repression capacity. These data expand the molecular consequences of Dicer1 hotspot mutations in cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":578139,"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":0.9507,"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":348469,"name":"Seungjae Lee","orcid":"0000-0001-5626-9656","position":1,"is_corresponding":false},{"id":1487817,"name":"Dapeng Yang","orcid":"0000-0003-2375-211X","position":2,"is_corresponding":false},{"id":474948,"name":"Robert C. Rickert","orcid":"0000-0003-4292-1708","position":3,"is_corresponding":false},{"id":348825,"name":"Renfu Shang","orcid":"0000-0002-3361-3036","position":4,"is_corresponding":false},{"id":632575,"name":"Danwei Huangfu","orcid":"0000-0002-1145-6199","position":5,"is_corresponding":false},{"id":182940,"name":"Eric C Lai","orcid":"0000-0002-8432-5851","position":6,"is_corresponding":false},{"id":252897,"name":"David Jee","orcid":null,"position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:58:20.638044Z","pmid":"41279602","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":[]}