Models of miRNA-mediated repression. According to the stoichiometric model of miRNA function (left), Ago–miRNA complexes are stably associated with target mRNAs during repression, which results in mRNA destabilization (transparent black) and miRNA stabilization (opaque blue). When Agos are limiting, miRNAs compete for Ago loading, Ago-free miRNAs are destabilized (transparent red and green), and Ago-free mRNAs are stabilized (opaque black). According to the catalytic model of miRNA function (right), Ago–miRNA complexes are recruited to target mRNAs as in the stoichiometric model but Agos may dissociate from mRNA–miRNA duplexes, allowing (1) transient association of Agos with multiple miRNA–mRNA complexes during repression and (2) multiple rounds of miRNA loading and recruitment to target mRNAs (dashed lines). Thus Agos function as RNA chaperons (Wang et al. 2009a; Kwak and Tomari 2012) and are not limiting. In the catalytic model, Ago-free miRNAs are stabilized (opaque red, green, and blue) by binding to target mRNAs, and target mRNAs are destabilized (transparent black) when their miRNA recognition elements are occupied by miRNAs, allowing transient Ago binding. The catalytic model explains how substoichiometric amounts of Agos are capable of binding suprastoichiometric amounts of miRNAs and regulating suprastoichiometric amounts of miRNA recognition elements.
