RNA interference pathways (RNAi) are mediated by small sequence-specific RNA molecules that shut down gene expression by one of three mechanisms: translational repression; mRNA degradation; and heterochromatin formation. Cleavage is a sort of rapid degradation by both 5'-3' and 3'-5' exonucleases. A targeted mRNA has two possible outcomes:
|RISC Complex w/ siRNA||Base-pairs extensively with target mRNA and induces cleavage. Argonaut is responsible for cleavage of target RNA when perfect base-pairing occurs. Argonaut has two domains: PAZ (binds end of miRNA) and PIWI (nuclease activity).|
|RISC Complex w/ miRNA||Imperfect base-pairing with target mRNA results in inhibition of translation. If base-pairing is imperfect, several miRNA-RISC complexes must associate with the target mRNA. These inhibit translation, and the mRNA gradually becomes associated with P bodies that lead to its degradation by a unique and slow mechanism.|
miRNA and siRNA share the same cellular machinery downstream of their initial processing. Dicer cleaves long dsRNA into short fragments of ~20 nucleotides. One of the two strands of each fragment, known as the guide strand, is then incorporated into the RNA-induced silencing complex (RISC) (promoted by Dicer). A pre-miRNA consists of the RNA, Drosha and Pasha. Primary miRNA transcript cropped in nucleus by enzyme Drosha. Exported by exportin 5. dsRNA portion of this pre-miRNA is bound and cleaved by Dicer to produce the mature miRNA molecule that can be integrated into the RISC complex.