A parsimonious model for gene regulation by miRNAs

Abstract

MicroRNAs (miRNAs) and small interfering RNAs (siRNAs) act with the Argonaute family of proteins to regulate target messenger RNAs (mRNAs) posttranscriptionally. SiRNAs typically induce endonucleolytic cleavage of mRNA with near-perfect complementarity. For targets with less complementarity, both translational repression and mRNA destabilization mechanisms have been implicated in miRNA-mediated gene repression, although the timing, coupling, and relative importance of these events have not been determined. Here, we review gene-specific and global approaches that probe miRNA function and mechanism, looking for a unifying model. More systematic analyses of the molecular specificities of the core components coupled with analysis of the relative timing of the different events will ultimately shed light on the mechanism of miRNA-mediated repression.

Figure 1

Conformational changes in the Argonautes. (Top left) Comparison of apo-like (gray; PDB code 3DLB) and oligonucleotide-bound (blue; PDB code 3DLH) structures of bacterial Argonautes. (Top right) Comparison of the same oligonucleotide-bound (blue; PDB code 3DLH) and duplex-bound (pink; PDB code 3HXM) Argonautes. (Bottom) Conformational changes thought to reflect binding of miRNA and mRNA targets.

Figure 2

Model for miRNA-mediated silencing. Cartoon outlines the proposed streamlined model, beginning with recruitment of Argonaute and associated GW182 and involving potential interactions with mRNA m7G cap. These binding events ultimately lead to translational repression by blocking some early step in translation initiation. Deadenylation by CCR4:NOT1 may contribute to translational repression at an initial step. Lastly, after deadenylation, miRNA targeted mRNA may be subjected to degradation (consolidation) through recruitment of decapping complex (DCP1/2).