fig2

Figure 2. Comparison between the mechanism of action of genetically targeted mRNA degradation. A (left): ASO-mediated mRNA degradation through RNase H1 nucleolytic activity. ASO (green rod) binds to complementary sequences on mRNA. This heteroduplex induces RNase H binding and leads to mRNA cleavage. After mRNA cleavage, the mRNA fragments, ASO and RNase H are released from each other. Grey arrow: free ASO is recycled for binding to another mRNA on the target sequence, which induces a new cycle of RNase H binding and mRNA cleavage; B (right): siRNA-mediated mRNA degradation. Double-stranded homoduplex siRNA is recruited by the RISC complex. The passenger “sense” strand (red rod) is released from the complex. The guide strand (green rod) remains positioned in the RISC complex and stabilizes it on the targeted complementary mRNA sequence by Watson-Crick hybridization. This induces mRNA cleavage. The cleaved mRNA is dissociated, and the RISC/guide siRNA complex can associate and cleave another mRNA (grey arrow).