title: A role of uridylation pathway for blockade of let-7 microRNA biogenesis by Lin28B.
abstract: The precise control of microRNA (miRNA) biosynthesis is crucial for gene regulation. Lin28A and Lin28B are selective inhibitors of biogenesis of let-7 miRNAs involved in development and tumorigenesis. Lin28A selectively inhibits let-7 biogenesis through cytoplasmic uridylation of precursor let-7 by TUT4 terminal uridyl transferase and subsequent degradation by Dis3l2 exonuclease. However, a role of this uridylation pathway remains unclear in let-7 blockade by Lin28B, a paralog of Lin28A, while Lin28B is reported to engage a distinct mechanism in the nucleus to suppress let-7. Here we revisit a functional link between Lin28B and the uridylation pathway with a focus on let-7 metabolism in cancer cells. Both Lin28A and Lin28B interacted with Dis3l2 in the cytoplasm, and silencing of Dis3l2 upregulated uridylated pre-let-7 in both Lin28A- and Lin28B-expressing cancer cell lines. In addition, we found that amounts of let-7 precursors influenced intracellular localization of Lin28B. Furthermore, we found that MCPIP1 (Zc3h12a) ribonuclease was also involved in degradation of both non-uridylated and uridylated pre-let-7. Cancer transcriptome analysis showed association of expression levels of Lin28B and uridylation pathway components, TUT4 and Dis3l2, in various human cancer cells and hepatocellular carcinoma. Collectively, these results suggest that cytoplasmic uridylation pathway actively participates in blockade of let-7 biogenesis by Lin28B.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi I
authors.initials: HI
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Katsura
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005095:Exoribonucleases / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C511130:TUT4 protein, human; D014157:Transcription Factors; C487931:mirnlet7 microRNA, human; C571454:DIS3L2 protein, human; D005095:Exoribonucleases; D012260:Ribonucleases; C510646:ZC3H12A protein, human
keywords: Biogenesis; Dis3l2; Lin28B; MCPIP1; let-7