title: Rbfox proteins regulate microRNA biogenesis by sequence-specific binding to their precursors and target downstream Dicer.
abstract: Rbfox proteins regulate tissue-specific splicing by targeting a conserved GCAUG sequence within pre-mRNAs. We report here that sequence-specific binding of the conserved Rbfox RRM to miRNA precursors containing the same sequence motif in their terminal loops, including miR-20b and miR-107, suppresses their nuclear processing. The structure of the complex between precursor miR-20b and Rbfox RRM shows the molecular basis for recognition, and reveals changes in the stem-loop upon protein binding. In mammalian cells, Rbfox2 downregulates mature miR-20b and miR-107 levels and increases the expression of their downstream targets PTEN and Dicer, respectively, suggesting that Rbfox2 indirectly regulates many more cellular miRNAs. Thus, some of the widespread cellular functions of Rbfox2 protein are attributable to regulation of miRNA biogenesis, and might include the mis-regulation of miR-20b and miR-107 in cancer and neurodegeneration.
authors.affiliation: Center for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento (TN), Italy.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195-1700, USA.
authors.forename: Lorena
authors.initials: L
authors.lastname: Zubovic
authors.affiliation: Center for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento (TN), Italy.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Center for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento (TN), Italy.
authors.forename: Katherine
authors.initials: K
authors.lastname: Godin
authors.affiliation: Center for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento (TN), Italy.
authors.forename: Tom
authors.initials: T
authors.lastname: Pavelitz
authors.affiliation: Center for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento (TN), Italy.
authors.forename: Javier
authors.initials: J
authors.lastname: Castellanos
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195-1700, USA paolo.macchi@unitn.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Macchi
authors.affiliation: Center for Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento (TN), Italy varani@chem.washington.edu.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Varani
mesh_terms: D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D000072260:RNA Splicing Factors / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D043244:Ribonuclease III / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: C549045:MIRN107 microRNA, human; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; D012097:Repressor Proteins; C408087:DICER1 protein, human; D043244:Ribonuclease III; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053487:DEAD-box RNA Helicases