A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity.
A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity.
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DOI：
10.1126/science.1190809
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发表时间：
2010-06-25
期刊：
影响因子：
--
通讯作者：
Giraldez AJ
中科院分区：
文献类型：
--
作者：
Cifuentes D;Xue H;Taylor DW;Patnode H;Mishima Y;Cheloufi S;Ma E;Mane S;Hannon GJ;Lawson ND;Wolfe SA;Giraldez AJ
Dicer是微小RNA（miRNA）加工过程中的一种关键酶。我们发现了一种不依赖Dicer的miRNA生物发生途径，该途径利用Argonaute2（Ago2）的切割酶催化活性。与其他miRNA不同，miR - 451的水平不受Dicer功能缺失的影响，但在MZago2（母源 - 合子）突变体中降低。我们发现体内pre - miR - 451的加工需要Ago2的催化活性。MZago2突变体表现出红细胞生成延迟，这种延迟可通过野生型Ago2或miR - 451双链体挽救，但不能通过无催化活性的Ago2挽救。改变依赖Dicer的miRNA的二级结构以模拟pre - miR - 451的结构，可恢复miRNA的功能并挽救MZdicer突变体的发育缺陷，这表明pre - miRNA的二级结构决定了体内的加工途径。我们提出，Ago2介导的pre - miRNA切割，随后进行尿苷化和修剪，可独立于Dicer产生有功能的miRNA。
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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