RNA interference pathway components (RNAi)

The RNA interference (RNAi) pathway is a fundamental cellular mechanism for sequence-specific post-transcriptional gene silencing, mediated by small RNA molecules (Fire & Mello, Nature, 1998). The pathway's core components include the RNase III enzyme Dicer, which cleaves long double-stranded RNA (dsRNA) into small interfering RNAs (siRNAs), and the RNA-induced silencing complex (RISC), which incorporates one strand of the siRNA to recognize and degrade complementary messenger RNA (mRNA) (Wilson & Doudna, Annu Rev Biophys, 2013). The Argonaute-2 (AGO2) protein is the catalytic engine of RISC, responsible for the endonucleolytic cleavage of target transcripts (UniProt P0C0U1). While the pathway naturally regulates gene expression via microRNAs (miRNAs), it has been harnessed therapeutically using synthetic siRNAs to silence disease-causing genes (Setten et al., Nat Rev Drug Discov, 2019). Approved drugs like Patisiran and Inclisiran utilize this machinery to treat hereditary transthyretin-mediated amyloidosis and hypercholesterolemia, respectively (FDA, 2018; FDA, 2021). Challenges in utilizing this pathway include ensuring efficient cytosolic delivery, avoiding off-target hybridization, and preventing the saturation of endogenous RNAi machinery which could disrupt normal cellular functions (Khan et al., Nature Genetics, 2009).

Other names

RNAi machineryRNA silencing componentsPost-transcriptional gene silencing (PTGS) machineryRISC complex components

RNA interference-mediated mRNA cleavage and degradation via the RISC complex.