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Target-specific requirements for enhancers of decapping in miRNA-mediated gene silencing

¹ Max Planck Institute for Developmental Biology, D-72076 Tübingen, Germany; ² German Cancer Research Center (DKFZ), Boveri-Group Signaling and Functional Genomics, D-69120 Heidelberg, Germany; ³ European Molecular Biology Laboratory (EMBL), D-69117 Heidelberg, Germany

microRNAs (miRNAs) silence gene expression by suppressing protein production and/or by promoting mRNA decay. To elucidate how silencing is accomplished, we screened an RNA interference library for suppressors of miRNA-mediated regulation in Drosophila melanogaster cells. In addition to proteins known to be required for miRNA biogenesis and function (i.e., Drosha, Pasha, Dicer-1, AGO1, and GW182), the screen identified the decapping activator Ge-1 as being required for silencing by miRNAs. Depleting Ge-1 alone and/or in combination with other decapping activators (e.g., DCP1, EDC3, HPat, or Me31B) suppresses silencing of several miRNA targets, indicating that miRNAs elicit mRNA decapping. A comparison of gene expression profiles in cells depleted of AGO1 or of individual decapping activators shows that 15% of AGO1-targets are also regulated by Ge-1, DCP1, and HPat, whereas 5% are dependent on EDC3 and LSm1–7. These percentages are underestimated because decapping activators are partially redundant. Furthermore, in the absence of active translation, some miRNA targets are stabilized, whereas others continue to be degraded in a miRNA-dependent manner. These findings suggest that miRNAs mediate post-transcriptional gene silencing by more than one mechanism.

[Keywords: Argonaute; decapping activators; decapping; miRNAs; mRNA decay; P-bodies; varicose]

Received June 1, 2007; revised version accepted August 16, 2007.

⁵ Present address: Institute of Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

⁶ Corresponding author.

E-MAIL elisa.izaurralde{at}tuebingen.mpg.de; FAX 49-7071-601-1353.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.443107

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