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      Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in embryonic stem cells

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          Abstract

          Lin28 and Lin28B, two developmentally regulated RNA-binding proteins and proto-oncogenes, selectively inhibit the maturation of let-7 family miRNAs in embryonic stem (ES) cells and certain cancers. Moreover, let-7 precursors (pre-let-7) were previously found to be terminally uridylated in a Lin28-dependent fashion. Here, we identify Zcchc11 (zinc finger, CCHC domain containing 11) as the 3′ terminal uridylyl transferase (TUTase) responsible for Lin28-mediated pre-let-7 uridylation and blockade of let-7 processing in mouse ES cells. We demonstrate that Zcchc11 activity is UTP-dependent, selective for let-7, and recruited by Lin28. Furthermore, knockdown of either Zcchc11 or Lin28, or overexpression of a catalytically inactive TUTase, relieves the selective inhibition of let-7 processing and leads to the accumulation of mature let-7 miRNAs and repression of let-7 target reporter genes. Our results establish a novel role for Zcchc11-catalyzed pre-let-7 uridylation in the control of miRNA biogenesis.

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          Selective blockade of microRNA processing by Lin28.

          S. Viswanathan, G Daley, R. I. Gregory (2008)
          MicroRNAs (miRNAs) play critical roles in development, and dysregulation of miRNA expression has been observed in human malignancies. Recent evidence suggests that the processing of several primary miRNA transcripts (pri-miRNAs) is blocked posttranscriptionally in embryonic stem cells, embryonal carcinoma cells, and primary tumors. Here we show that Lin28, a developmentally regulated RNA binding protein, selectively blocks the processing of pri-let-7 miRNAs in embryonic cells. Using in vitro and in vivo studies, we found that Lin28 is necessary and sufficient for blocking Microprocessor-mediated cleavage of pri-let-7 miRNAs. Our results identify Lin28 as a negative regulator of miRNA biogenesis and suggest that Lin28 may play a central role in blocking miRNA-mediated differentiation in stem cells and in certain cancers.
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            Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA.

            Inha Heo, Chirlmin Joo, Jun Soo Cho … (2008)
            The precise control of microRNA (miRNA) biogenesis is critical for embryonic development and normal cellular functions, and its dysregulation is often associated with human diseases. Though the birth and maturation pathway of miRNA has been established, the regulation and death pathway remains largely unknown. Here, we report the RNA-binding proteins, Lin28a and Lin28b, as posttranscriptional repressors of let-7 miRNA biogenesis. We observe that the Lin28 proteins act mainly in the cytoplasm by inducing uridylation of precursor let-7 (pre-let-7) at its 3' end. The uridylated pre-let-7 (up-let-7) fails Dicer processing and undergoes degradation. We provide a mechanism for the posttranscriptional regulation of miRNA biogenesis by Lin28 which is highly expressed in undifferentiated cells and certain cancer cells. The Lin28-mediated downregulation of let-7 may play a key role in development, stem cell programming, and tumorigenesis.
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              Lin28 Enhances Tumorigenesis and is Associated With Advanced Human Malignancies

              Srinivas R. Viswanathan, John Powers, William Einhorn … (2009)
              Multiple members of the let-7 family of miRNAs are often repressed in human cancers1,2, thereby promoting oncogenesis by de-repressing the targets K-Ras, c-Myc, and HMGA2 3,4. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins Lin28 and Lin28B block let-7 precursors from being processed to mature miRNAs5–8, suggesting that over-expression of Lin28/Lin28B might promote malignancy via repression of let-7. Here we show that LIN28 and LIN28B are over-expressed in primary human tumors and human cancer cell lines (overall frequency ∼15%), and that over-expression is linked to repression of let-7 family miRNAs and de-repression of let-7 targets. Lin28/Lin28B facilitate cellular transformation in vitro, and over-expression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28/LIN28B with poor clinical prognosis.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101186374
                Journal ID (pubmed-jr-id): 31761
                Journal ID (nlm-ta): Nat Struct Mol Biol
                Title: Nature structural & molecular biology
                ISSN (Print): 1545-9993
                ISSN (Electronic): 1545-9985
                Publication date Nihms-submitted: 24 August 2009
                Publication date (Electronic): 27 August 2009
                Publication date (Print): October 2009
                Publication date PMC-release: 1 April 2010
                Volume: 16
                Issue: 10
                Pages: 1021-1025
                Affiliations
                [1 ]Stem Cell Program, Children’s Hospital Boston Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School Harvard Stem Cell Institute Boston, MA 02115
                [2 ]Department of Molecular Virology, Immunology, and Medical Genetics College of Medicine The Ohio State University Medical Center Columbus, OH 43210
                Author notes
                [*]

                equal contribution

                [3 ]corresponding author: Richard I. Gregory Phone: (617) 919-2273 Fax: (617) 730-0748 rgregory@ 123456enders.tch.harvard.edu

                J.P.H. and E.P. contributed equally to this work.

                AUTHOR CONTRIBUTIONS J.P.H. and E.P. performed all experiments, J.P.H., E.P., and R.I.G., designed all experiments, analyzed data and wrote the manuscript.

                Article
                Manuscript ID: nihpa140663
                DOI: 10.1038/nsmb.1676
                PMC ID: 2758923
                PubMed ID: 19713958
                SO-VID: 6e97f9e2-e548-4207-80ba-af9761961518
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM086386-01A1 ||GM
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: microrna (mirna),lin28,lin-28,let-7,uridylation,tutase,zcchc11,3′ terminal uridylyl transferase
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: microrna (mirna), lin28, lin-28, let-7, uridylation, tutase, zcchc11, 3′ terminal uridylyl transferase

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