Schematic representation of the canonical and Dicer-independent miRNA biogenesis pathways. miRNAs are transcribed in the nucleus into primary transcripts. The RNase III enzyme Drosha processes the transcript to a stem-loop-structured precursor (pre-miRNA), which is exported to the cytoplasm. In the canonical pathway, illustrated here by the processing of pre-miR-144, the stem-loop structure of the precursor is recognized by Dicer, another RNase III, and cleaved into a double-stranded short RNA molecule 20 to 25 nucleotides long. The typical Dicer cleavage product features 5' phosphate groups and two-nucleotide overhangs at the 3' ends. The mature miRNA strand is loaded onto an Ago protein, while the other strand is released and degraded. In contrast, the precursor of miR-451 is recognized directly by Ago2. The unusual structure of the precursor (short stem, miRNA sequence spans the loop) promotes binding and cleavage by Ago2 after the 30th nucleotide. Therefore, miR-451 is produced independently of Dicer. The miRNA is further matured by so far unknown mechanisms.