A Novel miRNA Processing Pathway Independent of Dicer Requires Argonaute2 Catalytic Activity

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Science  06 May 2010:
DOI: 10.1126/science.1190809


Dicer is a central enzyme in miRNA processing. Here, we identify a Dicer-independent miRNA biogenesis pathway that employs Argonaute2 (Ago2) slicer catalytic activity. In contrast to other miRNAs, miR-451 levels were refractory to dicer loss-of-function but were reduced in MZago2 mutants. We show that pre-miR-451 processing requires Ago2 catalytic activity in vivo. MZago2 mutants showed delayed erythropoiesis that could be rescued by wild-type Ago2 or miR-451-duplex but not catalytically dead Ago2. Changing the secondary structure of dicer-dependent miRNAs to mimic that of pre-miR-451 restored miRNA function and rescued developmental defects in MZdicer mutants, indicating that the pre-miRNA secondary structure determines the processing pathway in vivo. We propose that Ago2-mediated cleavage of pre-miRNAs followed by uridylation and trimming generates functional miRNAs independently of Dicer.