Fig. 3

Schematic overview of the biogenesis and mechanism of action of miRNAs. MiRNAs encoded in introns of protein-coding genes and intergenic areas are initially transcribed by RNA Pol II in the nucleus. In the canonical pathway (left), pri-miRNAs are recognized and processed by the microprocessor complex, consisting of two RNase III enzymes, Drosha and DGCR8, releasing hairpin-structured pre-miRNAs. In the noncanonical pathway (right), however, pre-miRNA hairpins are generated from introns that undergo splicing and debranching, bypassing the step of Drosha cleavage. The nuclear export of pre-miRNAs is mediated by Exportin-5 in complex with Ran-GTP. Cytoplasmic pre-miRNAs are further cleaved by the endonuclease Dicer, aided by TRBP, to yield ~22-nucleotide miRNA duplexes. One strand of the duplex (the guide strand) is retained as mature miRNA and incorporated into RISC (containing AGO proteins), whereas the other strand (the passenger strand) is degraded. Mature miRNAs fine-tune gene expression by guiding RISC interaction with complementary sites of target mRNAs. The mechanisms of miRNA-mediated gene silencing, including accelerated cleavage and restricted translation of mRNAs, seem to largely depend on the degree of complementarity between seed sequences of miRNAs and the 3’ UTRs of target mRNAs. miRNA microRNA, Pol II RNA polymerase II, pri-miRNA primary transcript, DGCR8 DiGeorge syndrome critical region gene 8, pre-miRNA precursor miRNA, TRBP TAR RNA-binding protein, RISC RNA-induced silencing complex, AGO Argonaute, 3′ UTR 3′ untranslated region