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Autoregulation of microRNA biogenesis by let-7 and Argonaute

机译:let-7和Argonaute对microRNA生物发生的自动调节

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摘要

MicroRNAs (miRNAs) comprise a large family of small RNA molecules that post-transcriptionally regulate gene expression in many biological pathways. Most miRNAs are derived from long primary transcripts that undergo processing by Drosha to produce ~65-nucleotide precursors that are then cleaved by Dicer, resulting in the mature 22-nucleotide forms. Serving as guides in Argonaute protein complexes, mature miRNAs use imperfect base pairing to recognize sequences in messenger RNA transcripts, leading to translational repression and destabilization of the target messenger RNAs. Here we show that the miRNA complex also targets and regulates non-coding RNAs that serve as substrates for the miRNA-processing pathway. We found that the Argonaute protein in Caenorhabditis elegans, ALG-1, binds to a specific site at the 3' end of let-7 miRNA primary transcripts and promotes downstream processing events. This interaction is mediated by mature let-7 miRNA through a conserved complementary site in its own primary transcript, thus creating a positive-feedback loop. We further show that ALG-1 associates with let-7 primary transcripts in nuclear fractions. Argonaute also binds let-7 primary transcripts in human cells, demonstrating that the miRNA pathway targets non-coding RNAs in addition to protein-coding messenger RNAs across species. Moreover, our studies in C. elegans reveal a novel role for Argonaute in promoting biogenesis of a targeted transcript, expanding the functions of the miRNA pathway in gene regulation. This discovery of autoregulation of let-7 biogenesis establishes a new mechanism for controlling miRNA expression.%微RNA(rniRNA)与信使RNA发生相互作用来抑制基因表达。Amy Pasquinelli及其同事现在报告,miRNA还可以其他非编~-SRNA为目标。在线虫中,结合到Argonaute蛋白ALG-1上的成熟的Lef-7 miRNA在lef-7前体的3'端发生相互作用,促进其处理,形成一个正反馈环。这一发现首次为miRNA-loaded的Argorlaute蛋白在细rn胞核中确定了一个功能
机译:MicroRNA(miRNA)包含大量的小RNA分子家族,它们在许多生物途径中转录后调节基因表达。大多数miRNA都来自长的初级转录本,这些转录本经过Drosha加工后产生〜65个核苷酸的前体,然后被Dicer切割,形成成熟的22个核苷酸形式。作为Argonaute蛋白复合物的指导,成熟的miRNA使用不完善的碱基配对来识别信使RNA转录物中的序列,从而导致翻译抑制和目标信使RNA的不稳定。在这里,我们显示miRNA复合物还靶向并调节非编码RNA,这些非编码RNA充当miRNA加工途径的底物。我们发现秀丽隐杆线虫中的Argonaute蛋白ALG-1与let-7 miRNA初级转录本3'端的特定位点结合并促进下游加工事件。这种相互作用是由成熟的let-7 miRNA通过其自身原始转录物中一个保守的互补位点介导的,从而形成一个正反馈环。我们进一步表明,ALG-1与let-7初级转录本在核级分中相关联。 Argonaute还与人类细胞中的let-7初级转录物结合,表明miRNA途径除了跨物种的蛋白质编码信使RNA外,还靶向非编码RNA。此外,我们在秀丽隐杆线虫中的研究揭示了Argonaute在促进靶向转录物的生物发生,扩展miRNA途径在基因调控中的功能方面的新作用。 let-7生物发生的自动调节的发现为控制miRNA的表达建立了新的机制。%微RNA(rniRNA)与信使RNA发生相互作用来抑制基因表达。艾米·帕斯奎内利及其同事现在报告,miRNA还可以其他非编〜 -SRNA为目标。在线虫中,结合到Argonaute蛋白ALG-1上的成熟的Lef-7 mile在lef-7前体的3'端发生相互作用,促进其处理,形成一个正反馈环。发现首次为miRNA-loaded的Argorlaute蛋白在细rn胞核中确定了一个功能

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  • 来源
    《Nature》 |2012年第7404期|p.541-544a1|共5页
  • 作者单位

    Division of Biology, University of California, San Diego, La Jolla, California 92093-0349, USA;

    Division of Biology, University of California, San Diego, La Jolla, California 92093-0349, USA;

    Division of Biology, University of California, San Diego, La Jolla, California 92093-0349, USA,Department of Biology Education, Stockholm University, 106 91 Stockholm, Sweden;

    Division of Biology, University of California, San Diego, La Jolla, California 92093-0349, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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