Fig. 1 miRNA biogenesis and mechanism of function . Pre-miRNAs are transcribed from the miRNA gene by RNA polymerase enzyme in the nucleus. They are processed by Drosha (RNase III enzyme) and Pasha (DGCR8) to give pre-miRNA transcripts of ~70 nucleotides length, which form stem-loop structures. Pre-miRNAs are exported to the cytoplasm, where they are processed by Dicer (RNase II enzyme) and then loaded into the mRISC complex containing the Argonaute (Ago) proteins. miRNA in the mRISC complex is guided by Ago towards the binding site in the target 3’UTR. After binding to the target mRNA, target repression occurs via mRNA degradation or translation based on the complementarity between the mRNA and miRNA seed sequence2,3,49.
miRNAs in the mRISC complex then recognizes the target mRNA and directs it for decay and/or translation repression along with other RNA binding proteins (Fig. 1 ).2,3,49 The m7GTP cap structure in the 5’ end and poly-A tail in the ‘3’end of mRNA is important to initiate translation in eukaryotes.50 MicroRNAs are known to inhibit various stages of the translation process such as initiation, elongation, and maturation. The eukaryotic initiation factor complex consisting of eiF4F, eiF4G and eiF4A) recognizes and binds to the cap structure in the 5’end and recruits a small 40s ribosomal unit for translation. During translation, Poly A binding protein (PABP) recruited by GW182 binds to the poly-A tail present in the 3’end of mRNA and eiF4G interacts with PABP to circularize the mRNA.2,50 Binding of RISC complex with miRNA to the mRNA disrupts the interaction between eiF4F and PABP, causes decapping and deadenylation of the mRNA, which eventually leads to mRNA decay.2,51 Modeling these detailed events is not easy with limited quantitative experimental data. However, attempts have been made to model other features of miRNA regulation dealing with factors such as binding site complementarity, the number of binding sites, the relative abundance of miRNA and mRNA, presence of competing RNAs and RISC binding proteins, which influence the efficiency of miRNA mediated target repression effectively.52–55