title: Lin28a uses distinct mechanisms of binding to RNA and affects miRNA levels positively and negatively.
abstract: Lin28a inhibits the biogenesis of let-7 miRNAs by triggering the polyuridylation and degradation of their precursors by terminal uridylyltransferases TUT4/7 and 3'-5' exoribonuclease Dis3l2, respectively. Previously, we showed that Lin28a also controls the production of neuro-specific miRNA-9 via a polyuridylation-independent mechanism. Here we reveal that the sequences and structural characteristics of pre-let-7 and pre-miRNA-9 are eliciting two distinct modes of binding to Lin28a. We present evidence that Dis3l2 controls miRNA-9 production. Finally, we show that the constitutive expression of untagged Lin28a during neuronal differentiation in vitro positively and negatively affects numerous other miRNAs. Our findings shed light on the role of Lin28a in differentiating cells and on the ways in which one RNA-binding protein can perform multiple roles in the regulation of RNA processing.
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom.
authors.forename: Jakub Stanislaw
authors.initials: JS
authors.lastname: Nowak
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London, WC1E 6XA, United Kingdom.
authors.forename: Fruzsina
authors.initials: F
authors.lastname: Hobor
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Downie Ruiz Velasco
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom.
authors.forename: Nila Roy
authors.initials: NR
authors.lastname: Choudhury
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom.
authors.forename: Gregory
authors.initials: G
authors.lastname: Heikel
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom.
authors.forename: Alastair
authors.initials: A
authors.lastname: Kerr
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London, WC1E 6XA, United Kingdom.
authors.forename: Andres
authors.initials: A
authors.lastname: Ramos
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom.
authors.forename: Gracjan
authors.initials: G
authors.lastname: Michlewski
mesh_terms: D000818:Animals; D020029:Base Pairing; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005095:Exoribonucleases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011072:Poly U / Q000378:metabolism; D011485:Protein Binding; D059367:RNA Cleavage; D012316:RNA Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C511130:TUT4 protein, human; C487931:mirnlet7 microRNA, human; D049452:Green Fluorescent Proteins; D011072:Poly U; D014212:Tretinoin; D012316:RNA Nucleotidyltransferases; C576505:TUT7 protein, human; C571454:DIS3L2 protein, human; D005095:Exoribonucleases
keywords: Lin28a; let-7; miRNA-9; neuronal differentiation