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

Nat Struct Mol Biol. 2009 Oct;16(10):1016-20. doi: 10.1038/nsmb.1675. Epub 2009 Aug 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Base Sequence
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / physiology*
  • Cell Differentiation
  • Gene Expression Regulation*
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Models, Biological
  • Molecular Sequence Data
  • Nucleotidyltransferases / metabolism
  • Nucleotidyltransferases / physiology*
  • RNA Processing, Post-Transcriptional
  • Repressor Proteins / genetics*
  • Repressor Proteins / physiology*
  • Ribonuclease III / metabolism
  • Sequence Homology, Nucleic Acid


  • Caenorhabditis elegans Proteins
  • LIN-28 protein, C elegans
  • MicroRNAs
  • Repressor Proteins
  • let-7 microRNA, C elegans
  • Nucleotidyltransferases
  • poly U polymerase
  • Ribonuclease III