{"doi":"10.1101/2023.02.17.526327","title":"Discovery of novel microRNA mimic repressors of ribosome biogenesis","abstract":"Abstract While microRNAs and other non-coding RNAs are the next frontier of novel regulators of mammalian ribosome biogenesis (RB), a systematic exploration of microRNA-mediated RB regulation has not yet been undertaken. We carried out a high-content screen in MCF10A cells for changes in nucleolar number using a library of 2,603 mature human microRNA mimics. Following a secondary screen for nucleolar rRNA biogenesis inhibition, we identified 72 novel microRNA negative regulators of RB after stringent hit calling. Hits included 27 well-conserved microRNAs present in MirGeneDB, and were enriched for mRNA targets encoding proteins with nucleolar localization or functions in cell cycle regulation. Rigorous selection and validation of a subset of 15 microRNA hits unexpectedly revealed that most of them caused dysregulated pre-rRNA processing, elucidating a novel role for microRNAs in RB regulation. Almost all hits impaired global protein synthesis and upregulated CDKN1A ( p21 ) levels, while causing diverse effects on RNA Polymerase 1 (RNAP1) transcription and TP53 protein levels. We discovered that the MIR-28 siblings, hsa-miR-28-5p and hsa-miR-708-5p, directly and potently target the ribosomal protein mRNA RPS28 via tandem primate-specific 3’ UTR binding sites, causing a severe pre-18S pre-rRNA processing defect. Our work illuminates novel microRNA attenuators of RB, forging a promising new path for microRNA mimic chemotherapeutics. Graphical Abstract","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":395848,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":817220,"name":"Mason A. McCool","orcid":"0000-0001-7834-0927","position":1,"is_corresponding":false},{"id":1171635,"name":"Gabriela T. Rosado-González","orcid":null,"position":2,"is_corresponding":false},{"id":110491,"name":"Laura Abriola","orcid":"0000-0002-7304-6531","position":3,"is_corresponding":false},{"id":110492,"name":"Yulia V. Surovtseva","orcid":"0000-0001-6079-9246","position":4,"is_corresponding":false},{"id":409909,"name":"Susan J. Baserga","orcid":"0000-0002-7731-8629","position":5,"is_corresponding":false},{"id":724069,"name":"Carson J. Bryant","orcid":"0000-0002-7475-875X","position":0,"is_corresponding":true}],"reference_count":159,"raw_metadata":null,"created_at":"2026-07-19T01:19:27.044553Z","pmid":"36824951","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":[]}