How do miRNAs mediate translational repression?

Since their discovery 16 years ago, the prominent role that micro(mi)RNAs play as key post-transcriptional regulators of genetic networks is becoming more apparent. Although significant progress has been made in understanding the biogenesis and biological function of miRNAs [1], the mechanism of how miRNAs inhibit a particular mRNA is still unclear. Single-stranded mature miRNAs associate with Argonaute (Ago) proteins to form the core of a multicomponent gene regulatory complex named the RNA-induced silencing complex (RISC). Guided by the sequence complementarity between the small RNA and the target mRNA, miRNA-RISC-mediated gene inhibition is commonly divided into three processes: (i) site-specific cleavage, (ii) enhanced mRNA degradation and (iii) translational inhibition. The first process is restricted to miRNAs with a perfect or near-perfect match to the target RNA; this is commonly referred to as RNA interference (RNAi), and in mammals it is carried out exclusively by Ago2. By contrast, the other two processes are more commonly associated with mismatched miRNA/target sequences, which is the most likely scenario in mammals. The combination of these two processes is commonly referred to as non-cleavage repression, and can be carried out by any of the four mammalian Ago proteins [2]. Interestingly, recent genetic [3] and biochemical [4] studies have established that plant miRNAs also induce translational repression on their target mRNA, despite the near-perfect complementarity between the miRNA and target sequences, indicating that non-cleaving repression may be the default conserved function of miRNAs in these two kingdoms. It is not entirely clear if enhanced mRNA degradation and translational inhibitory events are mutually exclusive or perhaps more inter-related. Recent evidence suggests that the two processes are fundamentally independent but may overlap in some situations. Interestingly, in the presence of miRNAs, some target mRNAs can be exclusively repress