Major biogenesis pathways of small RNAs from inverted repeat transcripts in plants and animals. (a) In plants, canonical microRNAs (miRNAs) are produced by the nuclear RNase III Dicer-like1 (DCL1), which cuts from the base of the hairpin towards the loop; a subset of plant miRNAs are processed from the loop towards the hairpin. One miRNA/miRNA* duplex is shown, but there can be several such duplexes depending on the length of the stem. These are transported from the nucleus via HASTY, an Exportin5 (Exp5) homolog, for loading into an Argonaute (AGO) complex. The main miRNA effector in plants is AGO1, and to a lesser extent AGO10 and other AGOs; AGO7 carries the exceptional miRNA miR390. Long well-paired hairpins (proto-miR/inverted repeat (IR) transcripts) can be processed by a diversity of Dicers to generate either miRNAs or small interfering RNAs (siRNAs). The subcellular location for dicing by DCL2 and DCL4, and subsequent AGO loading of the resulting siRNAs, is not yet clear. nt, nucleotide. (b) In animals, canonical miRNAs are processed by the nuclear RNase III enzyme Drosha. The precursor miRNA (pre-miRNA) hairpin is exported to the cytoplasm by Exp5 to generate a single miRNA/miRNA* duplex, which is loaded into a miRNA class AGO protein (Drosophila dAGO1, Caenorhabditis elegans ALG1/2, or vertebrate Ago1 to Ago4). There are Drosha-independent non-canonical pathways, including the mirtron pathway where intron splicing and lariat debranching generate pre-miRNA hairpins. Also, vertebrate miR-451 is matured by a Dicer-independent route. Here, Drosha cleavage generates a short hairpin that is loaded into the 'Slicer' Ago2, which cleaves its 3' arm; this is resected to yield the mature miRNA. Unlike other vertebrate miRNAs, miR-451 can only be matured in Ago2. Finally, in the Drosophila hairpin RNA pathway, long inverted repeats are processed by the endogenous siRNA pathway, being cleaved by d-Dicer2 to generate siRNAs that load dAGO2. Many Drosophila miRNA* species are also preferentially sorted into dAGO2 (dashed arrow).
Axtell et al. Genome Biology 2011 12:221 doi:10.1186/gb-2011-12-4-221