LIN-28 and the poly(U) polymerase PUP-2 regulate let-7 microRNA processing in Caenorhabditis elegans View Full Text


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Article Info

DATE

2009-08-27

AUTHORS

Nicolas J. Lehrbach, Javier Armisen, Helen L. Lightfoot, Kenneth J. Murfitt, Anthony Bugaut, Shankar Balasubramanian, Eric A. Miska

ABSTRACT

The let-7 microRNA (miRNA) is an ultraconserved regulator of stem cell differentiation and developmental timing and a candidate tumor suppressor. Here we show that LIN-28 and the poly(U) polymerase PUP-2 regulate let-7 processing in Caenorhabditis elegans. We demonstrate that lin-28 is necessary and sufficient to block let-7 activity in vivo; LIN-28 directly binds let-7 pre-miRNA to prevent Dicer processing. Moreover, we have identified a poly(U) polymerase, PUP-2, which regulates the stability of LIN-28-blockaded let-7 pre-miRNA and contributes to LIN-28-dependent regulation of let-7 during development. We show that PUP-2 and LIN-28 interact directly, and that LIN-28 stimulates uridylation of let-7 pre-miRNA by PUP-2 in vitro. Our results demonstrate that LIN-28 and let-7 form an ancient regulatory switch, conserved from nematodes to humans, and provide insight into the mechanism of LIN-28 action in vivo. Uridylation by a PUP-2 ortholog might regulate let-7 and additional miRNAs in other species. Given the roles of Lin28 and let-7 in stem cell and cancer biology, we propose that such poly(U) polymerases are potential therapeutic targets. More... »

PAGES

1016-1020

References to SciGraph publications

  • 1998-02. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans in NATURE
  • 2009-05-10. 3′ uridylation precedes decapping in a novel pathway of bulk mRNA turnover in NATURE STRUCTURAL & MOLECULAR BIOLOGY
  • 2004-08-31. Microarray analysis of microRNA expression in the developing mammalian brain in GENOME BIOLOGY
  • 2009-03. Many roads to maturity: microRNA biogenesis pathways and their regulation in NATURE CELL BIOLOGY
  • 2008-07-06. A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment in NATURE CELL BIOLOGY
  • 2009-02. Biogenesis of small RNAs in animals in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2000-02. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans in NATURE
  • 2000-11. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA in NATURE
  • 2009-08-27. Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in embryonic stem cells in NATURE STRUCTURAL & MOLECULAR BIOLOGY
  • 2004-02. A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans in NATURE
  • 2009-07-05. A role for Lin28 in primordial germ cell development and germ cell malignancy in NATURE
  • 2000-11. Functional genomic analysis of C. elegans chromosome I by systematic RNA interference in NATURE
  • 2003-01. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi in NATURE
  • 2008-06-05. Improved northern blot method for enhanced detection of small RNA in NATURE PROTOCOLS
  • 2008-10-26. Single-copy insertion of transgenes in Caenorhabditis elegans in NATURE GENETICS
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nsmb.1675

    DOI

    http://dx.doi.org/10.1038/nsmb.1675

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/19713957


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    37 schema:description The let-7 microRNA (miRNA) is an ultraconserved regulator of stem cell differentiation and developmental timing and a candidate tumor suppressor. Here we show that LIN-28 and the poly(U) polymerase PUP-2 regulate let-7 processing in Caenorhabditis elegans. We demonstrate that lin-28 is necessary and sufficient to block let-7 activity in vivo; LIN-28 directly binds let-7 pre-miRNA to prevent Dicer processing. Moreover, we have identified a poly(U) polymerase, PUP-2, which regulates the stability of LIN-28-blockaded let-7 pre-miRNA and contributes to LIN-28-dependent regulation of let-7 during development. We show that PUP-2 and LIN-28 interact directly, and that LIN-28 stimulates uridylation of let-7 pre-miRNA by PUP-2 in vitro. Our results demonstrate that LIN-28 and let-7 form an ancient regulatory switch, conserved from nematodes to humans, and provide insight into the mechanism of LIN-28 action in vivo. Uridylation by a PUP-2 ortholog might regulate let-7 and additional miRNAs in other species. Given the roles of Lin28 and let-7 in stem cell and cancer biology, we propose that such poly(U) polymerases are potential therapeutic targets.
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