FIGURE 1 | Mechanism of RNA interference in mammalian cells.

RNA interference (RNAi) pathways are guided by small RNAs that include small interfering RNA (siRNA) and microRNAs (miRNAs). The siRNA pathway begins with cleavage of long double-stranded RNA (dsRNA) by the Dicer enzyme complex into siRNA. These siRNAs are incorporated into Argonaute 2 (AGO2) and the RNAi-induced silencing complex (RISC). If the RNA duplex loaded onto RISC has perfect sequence complementarity, AGO2 cleaves the passenger (sense) strand so that active RISC containing the guide (antisense) strand is produced. The siRNA guide strand recognizes target sites to direct mRNA cleavage (carried out by the catalytic domain of AGO2). RNAi therapeutics developed to harness the siRNA pathway typically involve the delivery of synthetic siRNA into the cell cytoplasm. The microRNA pathway begins with endogenously encoded primary microRNA transcripts (pri-miRNAs) that are transcribed by RNA polymerase II (Pol II) and are processed by the Drosha enzyme complex to yield precursor miRNAs (pre-miRNAs). These precursors are then exported to the cytoplasm by exportin 5 and subsequently bind to the Dicer enzyme complex, which processes the pre-miRNA for loading onto the AGO2–RISC complex. When the RNA duplex loaded onto RISC has imperfect sequence complementarity, the passenger (sense) strand is unwound leaving a mature miRNA bound to active RISC. The mature miRNA recognizes target sites (typically in the 3'-UTR) in the mRNA, leading to direct translational inhibition. Binding of miRNA to target mRNA may also lead to mRNA target degradation in processing (P)-bodies. Modified with permission from Nature Rev. Genet. Ref 5 © (2007) Macmillan Publishers Ltd.

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