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

By D. Cifuentes, Huiling Xue, David W. Taylor, Heather Patnode, Yuichiro Mishima, Sihem Cheloufi, E. Ma, Shrikant M. Mane, Gregory J. Hannon, Nathan D. Lawson and 2 more. Science, 2010

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No Dicer for Me MicroRNAs (miRNAs) are small noncoding RNAs found in most eukaryotes. Most are processed from primary transcripts in the nucleus by the microprocessor enzyme complex, which includes the nuclease Drosha, with a small number being generated by the messenger RNA splicing machinery. All pre-miRNAs are then exported into the cytoplasm where they are cleaved further by a second nuclease, Dicer, into the mature, functional miRNA. Cifuentes et al. (p. 1694, published online 6 May), now show that in a Dicer mutant fish at least one miRNA, miR-451, is still formed from pre-miR-451. The processing of pre-miR-451 requires the slicing activity of another protein in the miRNA pathway, Argonaute2. The unusual secondary structure of the pre-miR-451 determines its noncanonical processing pathway, which suggests that other miRNAs might also be processed in this way. The unusual secondary structure of a precursor microRNA determines its noncanonical processing. Dicer is a central enzyme in microRNA (miRNA) processing. We identified a Dicer-independent miRNA biogenesis pathway that uses 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 (maternal-zygotic) mutants. We found 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 by 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ab90e2c218124eaa0ca34739aba68f9216a3c0bf

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Citations in the corpus

The widespread regulation of microRNA biogenesis, function and decay (2010, background): “AGO2, but not Dicer, functions in processing of miR-451 and remains specifically associated with this miRN”
Metazoan MicroRNAs (2018, background): “In contrast to the other known noncanonical miRNAs, which require Dicer but not Drosha for their biogenesis (Figure 3B–”
Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs (2010, background): “Processing of the human miR-451 resulted in overlapping and loop-spanning mature miRNAs in a presumably ago2 mediated and Dicer independent mechanism (55,56).”
Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. (2012, methodology): “To identify sRNA-precursor lncRNAs, we compared our lncRNA transcripts to a set of sRNAs present in 2-d-old zebrafish (Methods; Cifuentes et al. 2010).”
MicroRNA: Biogenesis, Function and Role in Cancer (2010, background): “(2010) centers around the Argonaute 2 protein (Ago2), also known as eukaryotic translation initiation factor 2C2 (eIF2C2) [121].”
Evolution and Functional Diversification of MIRNA Genes (2011, background): “Although loop-distal processing occurs first during miRNA maturation of most foldbacks in plants and animals, alternative primary processing events have been characterized (Okamura et al., 2007; Ruby et al., 2007; Addo-Quaye et al., 2009; Bologna et al., 2009; Cheloufi et al., 2010; Cifuentes et al.”