Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis Journal Article
| Authors: | Yang, J. S.; Maurin, T.; Robine, N.; Rasmussen, K. D.; Jeffrey, K. L.; Chandwani, R.; Papapetrou, E. P.; Sadelain, M.; O'Carroll, D.; Lai, E. C. |
| Article Title: | Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis |
| Abstract: | Canonical animal microRNAs (miRNAs) are generated by sequential cleavage of precursor substrates by the Drosha and Dicer RNase III enzymes. Several variant pathways exploit other RNA metabolic activities to generate functional miRNAs. However, all of these pathways culminate in Dicer cleavage, suggesting that this is a unifying feature of miRNA biogenesis. Here, we show that maturation of miR-451, a functional miRNA that is perfectly conserved among vertebrates, is independent of Dicer. Instead, structure-function and knockdown studies indicate that Drosha generates a short pre-mir-451 hairpin that is directly cleaved by Ago2 and followed by resection of its 3′ terminus. We provide stringent evidence for this model by showing that Dicer knockout cells can generate mature miR-451 but not other miRNAs, whereas Ago2 knockout cells reconstituted with wild-type Ago2, but not Slicer-deficient Ago2, can process miR-451. Finally, we show that the mir-451 backbone is amenable to reprogramming, permitting vector-driven expression of diverse functional miRNAs in the absence of Dicer. Beyond the demonstration of an alternative strategy to direct gene silencing, these observations open the way for transgenic rescue of Dicer conditional knockouts. |
| Keywords: | controlled study; unclassified drug; human cell; genetics; nonhuman; molecular genetics; protein function; animal cell; mouse; animal; metabolism; mouse mutant; animals; mice; mice, knockout; microrna; gene expression; cell maturation; cell line; small interfering rna; rna, small interfering; hela cell; hela cells; mice, inbred c57bl; c57bl mouse; gene vector; animalia; vertebrata; dead box protein; rna; dead-box rna helicases; biosynthesis; chemistry; drug antagonism; conserved sequence; molecular sequence data; nucleotide sequence; base sequence; mutagenesis, site-directed; 3' untranslated region; gene silencing; dna primers; primer dna; conformation; nucleic acid conformation; protein structure; sequence homology; micrornas; sequence homology, nucleic acid; site directed mutagenesis; vertebrate; short hairpin rna; protein cleavage; biogenesis; nuclear reprogramming; dicer; ribonuclease iii; argonaute 2 protein; endoribonucleases; ribonuclease; gene suppression; mirna reprogramming; slicer; microrna 451; dicer1 protein, human; dicer1 protein, mouse; drosha protein, mouse; eif2c2 protein, human; eif2c2 protein, mouse; initiation factor 2; mirn451 microrna, human; mirn451 microrna, mouse; rnasen protein, human; eukaryotic initiation factor-2 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 107 |
| Issue: | 34 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2010-08-24 |
| Start Page: | 15163 |
| End Page: | 15168 |
| Language: | English |
| DOI: | 10.1073/pnas.1006432107 |
| PUBMED: | 20699384 |
| PROVIDER: | scopus |
| PMCID: | PMC2930549 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 5" - "Export Date: 20 April 2011" - "CODEN: PNASA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work