RNA interference

Messenger RNA (mRNA) carries information copied from a gene and can be used by cells to make protein. In RNA interference, short RNA sequences guide cellular protein complexes to matching RNA molecules. Depending on the organism and pathway, the target mRNA may be cut and degraded or its translation into protein may be reduced. The result is lower expression of the corresponding gene without necessarily changing its DNA sequence.

In a commonly described small-interfering-RNA pathway, double-stranded RNA is processed by the enzyme Dicer into short interfering RNAs (siRNAs). One strand is retained by the RNA-induced silencing complex (RISC), which includes an Argonaute protein. By pairing with a complementary sequence, the guide strand brings the complex to a target RNA; Argonaute can then cleave a sufficiently matched target, which is subsequently degraded. Related microRNAs are produced from endogenous RNA precursors and often regulate multiple targets, frequently by reducing translation as well as promoting mRNA turnover. Details vary among organisms and RNA-silencing pathways.

RNA silencing occurs across diverse eukaryotes. It can regulate gene activity and help defend genomes against viruses and mobile genetic elements such as transposons. Early observations included unexpected silencing in transgenic plants. In 1998, Andrew Fire and Craig Mello reported that double-stranded RNA could trigger potent, sequence-specific gene silencing in the nematode Caenorhabditis elegans, explaining a mechanism distinct from simply adding antisense RNA. They received the 2006 Nobel Prize in Physiology or Medicine for the discovery of RNA interference.

Experimental RNAi allows researchers to reduce expression of selected genes and study resulting cellular effects. This can reveal gene function, though incomplete silencing, unintended target effects, and differences between experimental models and organisms must be considered. Therapeutic RNAi aims to silence disease-associated transcripts using designed small RNAs delivered to relevant tissues. Some RNAi medicines have reached clinical use, while many potential applications remain under development. Delivery, stability, target choice, and off-target effects are important limitations.