![]() The siRNAs are loaded into Argonaute proteins which are at the center of the RNA-induced silencing complex (RISC). a) In “classical RNAi”, or the siRNA pathway, exogenous dsRNAs are processed into siRNAs by Dicer complexes. RNA interference pathways involving the Argonaute protein subfamily. TGS is best described in fission yeast where small RNAs and a specialized RISC complex (RITS) guide the formation of heterochromatin ( Figure 1c). Although controversial the miRNA silencing machinery directs targeted mRNAs into cytoplasmic foci called P-bodies, which are deprived of the translational machinery but retain proteins involved in mRNA degradation ( Figure 1b). PTGS also operates via translational repression induced by microRNAs (miRNA pathway) derived from hairpin precursors transcribed in the nucleus. The RNA induced silencing complex (RISC) is guided by a siRNA complementary to mRNA targets and catalyzes a mRNA cleavage event (slicing) leading to message degradation ( Figure 1a). One form of PTGS is induced by the introduction of long dsRNAs homologous to a target gene which produces small interfering RNAs (siRNA pathway). RNAi is accomplished through transcriptional (TGS) or post-transcriptional (PTGS) gene silencing (recently reviewed in ). Beyond the progress made in the basic research laboratory, RNAi technology is receiving deserved consideration as a clinical therapeutic strategy to specifically target genes associated with disease. RNA interference (RNAi), the process by which genes are silenced by small RNAs, is a rapidly emerging field of research with contributions from molecular biology, genetics, biochemistry, bioinformatics and structural biology. Interestingly SAGOs lack conserved Slicer amino acid residues and probably act in a Slicer-independent fashion. Secondary siRNAs are 5’ triphosphorylated which may allow specific loading into SAGO complexes that are rate limiting for RNAi in C. elegans is mediated by secondary siRNAs selectively bound to secondary Argonautes (SAGOs) that belong to a worm specific Argonaute subfamily (WAGO). Piwi/piRNA complexes in mammals and flies are directly linked to the control of transposable elements during germline development. Piwi-interacting RNAs (piRNAs) carry a 2’ O-methylation on their 3’ end and appear to be synthesized by a Piwi Slicer dependent mechanism. ![]() ![]() The Piwi subfamily functions in the germline through a novel class of small RNAs that are longer than Argonaute specific si- and miRNAs. Two recently described Argonaute protein subfamilies mediate distinct functions in RNAi. In the classical RNAi pathway Argonaute functions as the Slicer enzyme that cleaves a mRNA target directed by a complementary siRNA. Argonaute is at the heart of all effector complexes in RNA interference. ![]()
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