A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity.
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.
Cifuentes
Daniel
D
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Xue
Huiling
H
Taylor
David W
DW
Patnode
Heather
H
Mishima
Yuichiro
Y
Cheloufi
Sihem
S
Ma
Enbo
E
Mane
Shrikant
S
Hannon
Gregory J
GJ
Lawson
Nathan D
ND
Wolfe
Scot A
SA
Giraldez
Antonio J
AJ
D000818:Animals; D060565:Argonaute Proteins; D055162:Biocatalysis; D004625:Embryo, Nonmammalian / Q000378:metabolism; D047108:Embryonic Development; D004920:Erythropoiesis; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D009024:Morphogenesis; D009690:Nucleic Acid Conformation; D012322:RNA Precursors / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D011994:Recombinant Proteins / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
C466422:AGO2 protein, human; C550569:Ago2 protein, zebrafish; D060565:Argonaute Proteins; D015852:Eukaryotic Initiation Factor-2; D035683:MicroRNAs; C539470:Mirn451 microRNA, zebrafish; D012322:RNA Precursors; D011994:Recombinant Proteins; D029961:Zebrafish Proteins; D043244:Ribonuclease III
Cell. 2009 Feb 20;136(4):642-55
19239886
PLoS Biol. 2007 May;5(5):e132
17472439
Science. 2004 Sep 3;305(5689):1434-7
15284453
Science. 2001 Aug 10;293(5532):1146-50
11498593
Nat Chem Biol. 2007 Jan;3(1):36-43
17173028
Cell. 2007 Dec 14;131(6):1097-108
18083100
Cell. 2007 Jul 13;130(1):89-100
17599402
Mol Cell. 2007 Oct 26;28(2):328-36
17964270
Science. 2006 Apr 7;312(5770):75-9
16484454
Development. 1996 Dec;123:303-9
9007250
Science. 2004 Sep 3;305(5689):1437-41
15284456
Nucleic Acids Res. 2009 Dec;37(22):7533-45
19808937
Blood. 2009 Feb 19;113(8):1794-804
18849488
Nature. 2007 Jul 5;448(7149):83-6
17589500
Nature. 2010 Jun 3;465(7298):584-9
20424607
Nat Biotechnol. 2008 Jun;26(6):702-8
18500334
Cell. 2002 Sep 6;110(5):563-74
12230974
Nat Biotechnol. 2005 Feb;23(2):227-31
15619616
Cell. 2009 Jan 23;136(2):215-33
19167326
Mol Cell. 2008 Jul 25;31(2):294-301
18657511
Cell. 2005 Nov 18;123(4):607-20
16271386
Nat Struct Mol Biol. 2009 Dec;16(12):1259-66
19946268
Nat Genet. 2003 Nov;35(3):217-8
14528306
Nat Biotechnol. 2008 Jun;26(6):695-701
18500337
Nat Struct Mol Biol. 2010 Jan;17(1):5-10
20051982
Mol Cell. 2009 Nov 13;36(3):445-56
19917252
Genes Dev. 2008 Oct 15;22(20):2773-85
18923076