Summary of major characterized miRNA biogenesis pathways in animal cells. (A) Canonical miRNAs are produced by sequential cleavage by the RNase III enzymes Drosha and Dicer. Resultant miRNA/star duplexes load into miRNA effector Argonautes (Ago1–4 in mammals), and the active regulatory complex contains a single-stranded miRNA. (B) Several alternative miRNA biogenesis pathways bypass Drosha cleavage by exploiting the spliceosome (which processes introns), RNase Z (which processes tRNAs), and Integrator (which processes snRNAs); other sources of Drosha-independent miRNAs have also been described. (C) Vertebrate mir-451 has a short hairpin that is processed by Drosha but then bypasses Dicer. Instead, the pre-miRNA is directly loaded into Ago proteins; those that enter the sole catalytic member Ago2 are sliced on the 3′ arm and subsequently trimmed to yield mature miR-451.
