Discovery of novel microRNA mimic repressors of ribosome biogenesis.

Autor:	Bryant CJ; Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, 06520, USA., McCool MA; Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, 06520, USA., Rosado González GT; Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, 06520, USA., Abriola L; Yale Center for Molecular Discovery, Yale University, West Haven, CT, 06516, USA., Surovtseva YV; Yale Center for Molecular Discovery, Yale University, West Haven, CT, 06516, USA., Baserga SJ; Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, 06520, USA.; Department of Genetics, Yale School of Medicine, New Haven, CT, 06520, USA.; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, 06520, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2024 Feb 28; Vol. 52 (4), pp. 1988-2011.
DOI:	10.1093/nar/gkad1235
Abstrakt:	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 2603 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 provide evidence that the MIR-28 siblings, hsa-miR-28-5p and hsa-miR-708-5p, 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. (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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