MicroRNAs Silence Gene Expression by Repressing Protein Expression and/or by Promoting mRNA Decay

Abstract

microRNAs (miRNAs) represent a novel class of genome-encoded eukaryotic regulatory RNAs that silence gene expressionposttranscriptionally. Although the proteins mediating miRNA biogenesis and function have been identified, the precisemechanism by which miRNAs regulate the expression of target mRNAs remains unclear. We summarize recent work fromour laboratory demonstrating that miRNAs silence gene expression by at least two independent mechanisms: by repressingtranslation and/or by promoting mRNA degradation. In Drosophila, both mechanisms require Argonaute 1 (AGO1) and theP-body component GW182. Moreover, mRNA degradation by miRNAs is effected by the enzymes involved in generalmRNA decay, including deadenylases and decapping enzymes, which also localize to P bodies. Our findings suggest a modelfor miRNA function in which AGO1 associates with miRNA targets through miRNA:mRNA base-pairing interactions.GW182 interacts with AGO1 and recruits deadenylases and decapping enzymes, leading to mRNA degradation. However, notall miRNA targets are degraded: Some stay in a translationally silent state, from which they may eventually be released. Wepropose that the final outcome of miRNA regulation (i.e., degradation vs. translational repression) is influenced by otherRNA-binding proteins interacting with the targeted mRNA.