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PMID: 19713957 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature structural & molecular biology ·Vol. 16 ·No. 10 ·2009-10-00 ·Pages 1016-20

Lehrbach NJ, Armisen J, Lightfoot HL, Murfitt KJ, Bugaut A, Balasubramanian S, Miska EA

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.

MeSH Terms
Animals Animals, Genetically Modified Base Sequence Caenorhabditis elegans Caenorhabditis elegans Proteins/genetics,physiology Cell Differentiation Gene Expression Regulation MicroRNAs/genetics,metabolism Models, Biological Molecular Sequence Data Nucleotidyltransferases/metabolism,physiology RNA Processing, Post-Transcriptional Repressor Proteins/genetics,physiology Ribonuclease III/metabolism Sequence Homology, Nucleic Acid
Chemicals
Caenorhabditis elegans Proteins LIN-28 protein, C elegans MicroRNAs Repressor Proteins let-7 microRNA, C elegans Nucleotidyltransferases poly U polymerase Ribonuclease III
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Lehrbach Nicolas J
Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, The Henry Wellcome Building of Cancer and Developmental Biology, Cambridge, UK.
Armisen Javier
Lightfoot Helen L
Murfitt Kenneth J
Bugaut Anthony
Balasubramanian Shankar
Miska Eric A
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.1675
Published
2009-10-00
Epub
2009-00-27
Pages
1016-20
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC2988485
Subset
IM
Grants
Wellcome Trust · United Kingdom
Biotechnology and Biological Sciences Research Council · United Kingdom
Cancer Research UK · A11832 · United Kingdom
Cancer Research UK · 6934 · United Kingdom
Cancer Research UK · A6934 · United Kingdom
External Links
PubMed source DOI: 10.1038/nsmb.1675 PMC Full Text View journal details
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