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. Author manuscript; available in PMC: 2016 Feb 5.
Published in final edited form as: Nat Rev Drug Discov. 2012 Jan 20;11(2):125–140. doi: 10.1038/nrd3625

Figure 1. Mechanisms of oligonucleotide-induced downregulation of gene expression.

Figure 1

A. SiRNA. Synthetic double-stranded short interfering RNA (siRNA) is complexed with components of RNA interference (RNAi) pathway, dicer, AGO2 and other proteins, forming RNA-interference-silencing-complex, RISC. RISC binds to a target mRNA via the unwound guide strand of siRNA, allowing AGO 2 to degrade the RNA. RISC-bound siRNA can also bind with mismatches to unintended mRNAs, leading to significant off-target effects (see main text).

B. Antisense gapmer oligonucleotides. These usually have a PS backbone with flanks additionally modified with 2′MOE or 2′OMe residues (Red in figure. flank modifications increase resistance of the ASO to degradation and enhance binding to target mRNA. The unmodified “gap” in a gapmer/mRNA duplex is recognized by RNase H, a ribonuclease that degrades duplexed mRNA.

C. Translation suppressing oligomers (TSO). PMO and their derivatives or oligonucleotides fully substituted with 2′MOE or 2′OMe residues are not recognized by RISC or RNase H and do not lead to RNA degradation. Nevertheless, they lead to downregulation of gene expression by steric blockade of ribosome access to mRNA and suppression of protein translation.

D. External Guide Sequence (EGS) and RNase P. A PPMO is designed to hybridize to targeted bacterial mRNA and form stem-loop structures such that the resulting duplex resembles tRNA. In bacteria, a tRNA processing ribozyme RNase P recognizes this structure and cleaves mRNA.