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

Overview

Journal Science

Specialty Science

Date 2010 May 8

PMID 20448148

Citations 474

Authors

Daniel Cifuentes

Huiling Xue

David W Taylor

Heather Patnode

Yuichiro Mishima

Sihem Cheloufi

Enbo Ma

Shrikant Mane

Gregory J Hannon

Nathan D Lawson

Scot A Wolfe

Antonio J Giraldez

Affiliations

Soon will be listed here.

Abstract

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.

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References

Carthew R, Sontheimer E . Origins and Mechanisms of miRNAs and siRNAs. Cell. 2009; 136(4):642-55. PMC: 2675692. DOI: 10.1016/j.cell.2009.01.035. View

Qian F, Zhen F, Xu J, Huang M, Li W, Wen Z . Distinct functions for different scl isoforms in zebrafish primitive and definitive hematopoiesis. PLoS Biol. 2007; 5(5):e132. PMC: 1858710. DOI: 10.1371/journal.pbio.0050132. View

Song J, Smith S, Hannon G, Joshua-Tor L . Crystal structure of Argonaute and its implications for RISC slicer activity. Science. 2004; 305(5689):1434-7. DOI: 10.1126/science.1102514. View

Hammond S, Boettcher S, Caudy A, Kobayashi R, Hannon G . Argonaute2, a link between genetic and biochemical analyses of RNAi. Science. 2001; 293(5532):1146-50. DOI: 10.1126/science.1064023. View

Tolia N, Joshua-Tor L . Slicer and the argonautes. Nat Chem Biol. 2006; 3(1):36-43. DOI: 10.1038/nchembio848. View

Diederichs S, Haber D . Dual role for argonautes in microRNA processing and posttranscriptional regulation of microRNA expression. Cell. 2007; 131(6):1097-108. DOI: 10.1016/j.cell.2007.10.032. View

Okamura K, Hagen J, Duan H, Tyler D, Lai E . The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell. 2007; 130(1):89-100. PMC: 2729315. DOI: 10.1016/j.cell.2007.06.028. View

Berezikov E, Chung W, Willis J, Cuppen E, Lai E . Mammalian mirtron genes. Mol Cell. 2007; 28(2):328-36. PMC: 2763384. DOI: 10.1016/j.molcel.2007.09.028. View

Giraldez A, Mishima Y, Rihel J, Grocock R, van Dongen S, Inoue K . Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science. 2006; 312(5770):75-9. DOI: 10.1126/science.1122689. View

10.

Weinstein B, Schier A, Abdelilah S, Malicki J, Stemple D, Stainier D . Hematopoietic mutations in the zebrafish. Development. 1996; 123:303-9. DOI: 10.1242/dev.123.1.303. View

11.

Liu J, Carmell M, Rivas F, Marsden C, Thomson J, Song J . Argonaute2 is the catalytic engine of mammalian RNAi. Science. 2004; 305(5689):1437-41. DOI: 10.1126/science.1102513. View

12.

Tan G, Garchow B, Liu X, Yeung J, Morris 4th J, Cuellar T . Expanded RNA-binding activities of mammalian Argonaute 2. Nucleic Acids Res. 2009; 37(22):7533-45. PMC: 2794174. DOI: 10.1093/nar/gkp812. View

13.

Pase L, Layton J, Kloosterman W, Carradice D, Waterhouse P, Lieschke G . miR-451 regulates zebrafish erythroid maturation in vivo via its target gata2. Blood. 2008; 113(8):1794-804. PMC: 2647672. DOI: 10.1182/blood-2008-05-155812. View

14.

Ruby J, Jan C, Bartel D . Intronic microRNA precursors that bypass Drosha processing. Nature. 2007; 448(7149):83-6. PMC: 2475599. DOI: 10.1038/nature05983. View

15.

Cheloufi S, Dos Santos C, Chong M, Hannon G . A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature. 2010; 465(7298):584-9. PMC: 2995450. DOI: 10.1038/nature09092. View

16.

Doyon Y, McCammon J, Miller J, Faraji F, Ngo C, Katibah G . Heritable targeted gene disruption in zebrafish using designed zinc-finger nucleases. Nat Biotechnol. 2008; 26(6):702-8. PMC: 2674762. DOI: 10.1038/nbt1409. View

17.

Martinez J, Patkaniowska A, Urlaub H, Luhrmann R, Tuschl T . Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell. 2002; 110(5):563-74. DOI: 10.1016/s0092-8674(02)00908-x. View

18.

Siolas D, Lerner C, Burchard J, Ge W, Linsley P, Paddison P . Synthetic shRNAs as potent RNAi triggers. Nat Biotechnol. 2004; 23(2):227-31. DOI: 10.1038/nbt1052. View

19.

Bartel D . MicroRNAs: target recognition and regulatory functions. Cell. 2009; 136(2):215-33. PMC: 3794896. DOI: 10.1016/j.cell.2009.01.002. View

20.

Maeder M, Thibodeau-Beganny S, Osiak A, Wright D, Anthony R, Eichtinger M . Rapid "open-source" engineering of customized zinc-finger nucleases for highly efficient gene modification. Mol Cell. 2008; 31(2):294-301. PMC: 2535758. DOI: 10.1016/j.molcel.2008.06.016. View