Cell & Nature：miRNA最新发现

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Cell & Nature：miRNA最新发现 microRNAs是一种长21－25nt的单链小分子RNA，由于其在细胞生长和发育过程的调节作用而倍受科学家们的瞩目。近期来自英国和美国的科学家在这一小分子研究方面又获得重要进展，值得关注。对于miRNAs的研究起始于时序调控小RNA（stRNAs），由于miRNAs在物种进化中相当保守，在植物、动物和真菌中发现的miRNAs只在特定的组织和发育阶段表达，而且这种特异性和时序性，决定了组织和细胞的

  microRNAs是一种长21－25nt的单链小分子RNA，由于其在细胞生长和发育过程的调节作用而倍受科学家们的瞩目。近期来自英国和美国的科学家在这一小分子研究方面又获得重要进展，值得关注。  

  对于miRNAs的研究起始于时序调控小RNA（stRNAs），由于miRNAs在物种进化中相当保守，在植物、动物和真菌中发现的miRNAs只在特定的组织和发育阶段表达，而且这种特异性和时序性，决定了组织和细胞的功能特异性，表明miRNA在细胞生长和发育过程的调节过程中起多种作用，因此miRNA的研究受到了生物学家的广泛关注。

  siRNAs（Short interfering RNAs）相似于miRNAs，也是通过Dicer产生，但是其前体是完整的双链RNA。siRNAs能调控转录后修饰，以及表观基因组修饰，不同的真核生物，比如真菌，植物，原生动物和后生动物都能产生siRNAs，但是至今为止，在单细胞生物体中并未发现miRNAs，这让科学家们认为miRNAs是在进化上植物和动物多细胞生命形态出现之后才存在的。

  在Nature的这篇文章中，来自英国John Innes中心（John Innes Centre），东英格兰大学（University of East Anglia）的研究人员发现单细胞藻类：莱茵衣藻（Chlamydomonas reinhardtii）包含有miRNAs，miRNAs假设的进化上前体，以及与高等植物类似的siRNAs——莱茵衣藻是一种单细胞真核鞭毛藻类，是研究多种生命活动（如光合作用、鞭毛组装、趋光性和生理节律等）的模式生物，与酵母细胞有许多共同的特征，素有“光合酵母”之称。

  从这一研究中可以看出，藻类和高等植物中的miRNAs和siRNAs共同特点说明复杂RNA沉默系统在多细胞生命形态出现之前就存在了，是一种原始真核细胞的特征。

原始出处：

Nature advance online publication 30 May 2007 | doi:10.1038/nature05903; Received 21 February 2007; Accepted 2 May 2007; Published online 30 May 2007


miRNAs control gene expression in the single-cell alga Chlamydomonas reinhardtii
Attila Molnár1, Frank Schwach1,2, David J. Studholme1, Eva C. Thuenemann1 & David C. Baulcombe1

Sainsbury Laboratory, John Innes Centre, Norwich NR4 7UH, UK
University of East Anglia, School of Computing Sciences, Norwich NR4 7TJ, UK
Correspondence to: David C. Baulcombe1 Correspondence and requests for materials should be addressed to D.C.B. (Email: david.baulcombe@tsl.ac.uk).


Abstract

MicroRNAs (miRNAs) in eukaryotes guide post-transcriptional regulation by means of targeted RNA degradation and translational arrest1. They are released by a Dicer nuclease as a 21–24-nucleotide RNA duplex from a precursor in which an imperfectly matched inverted repeat forms a partly double-stranded region. One of the two strands is then recruited by an Argonaute nuclease that is the effector protein of the silencing mechanism. Short interfering RNAs (siRNAs), which are similar to miRNAs, are also produced by Dicer but the precursors are perfectly double-stranded RNA. These siRNAs guide post-transcriptional regulation, as with miRNAs, and epigenetic genome modification. Diverse eukaryotes including fungi, plants, protozoans and metazoans produce siRNAs2, 3, 4, 5 but, until now, miRNAs have not been described in unicellular organisms and it has been suggested that they evolved together with multicellularity in separate plant and animal lineages6. Here we show that the unicellular alga Chlamydomonas reinhardtii contains miRNAs, putative evolutionary precursors of miRNAs and species of siRNAs resembling those in higher plants. The common features of miRNAs and siRNAs in an alga and in higher plants indicate that complex RNA-silencing systems evolved before multicellularity and were a feature of primitive eukaryotic cells.

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  另一篇有关miRNAs的研究新进展则是围绕Argonaute蛋白展开，这篇发表在Cell网络版上的文章由美国宾州大学医学院医学系和病理学系的研究人员完成。

  Argonaute（Ago）蛋白是一个高度保守的家族，这一蛋白家族包括许多成员，它们组成了RNA诱导的沉默复合体的核心元件，是RNA干扰所必须的——Argonaute蛋白选择性地与miRNA和siRNA结合，并与Dicer酶相互作用，其PIWI盒子与Dicer的RNaseⅢ结构域直接相互作用，PIWI与Dicer之间的相互作用可能会促进miRNA/siRNA的释放。

  人类let-7miRNA以依赖于m7G cap的方式抑制mRNA靶标的翻译启动，以及蛋白的表达，但是其中的分子机制，以及其中Ago在翻译调控过程的作用至今并不清楚。

  在这篇文章中，研究人员在Ago蛋白中间区域发现了一个motif（MC），这个结构区域与eIF4E（翻译启动必需因子）的m7G帽结合结构域十分相似，而且他们也在人类Ago2的MC结构上发现了保守的芳香族残基，这对于绑定到m7G帽和翻译抑制是必需的，但是并不影响Ago与miRNA的组装或者Ago2的活性。因此研究认为Ago2通过结合到mRAN靶标m7G结构上来抑制mRNA的翻译，而排除了eIF4E重新募集的可能性。

原始出处：

Cell, Vol , Issue ,

Article

An mRNA m7G Cap Binding-like Motif within Human Ago2 Represses Translation
Marianthi Kiriakidou,1, Grace S. Tan,1 Styliani Lamprinaki,2,3 Mariangels De Planell-Saguer,2 Peter T. Nelson,2,4 and Zissimos Mourelatos2,

1 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
2 Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA


Corresponding author
Marianthi Kiriakidou
kiriakim@uphs.upenn.edu

Corresponding author
Zissimos Mourelatos
mourelaz@uphs.upenn.edu

Abstract

microRNAs (miRNAs) bind to Argonaute (Ago) proteins and inhibit translation or promote degradation of mRNA targets. Human let-7 miRNA inhibits translation initiation of mRNA targets in an m7G cap-dependent manner and also appears to block protein production, but the molecular mechanism(s) involved is unknown and the role of Ago proteins in translational regulation remains elusive. Here we identify a motif (MC) within the Mid domain of Ago proteins, which bears significant similarity to the m7G cap-binding domain of eIF4E, an essential translation initiation factor. We identify conserved aromatic residues within the MC motif of human Ago2 that are required for binding to the m7G cap and for translational repression but do not affect the assembly of Ago2 with miRNA or its catalytic activity. We propose that Ago2 represses the initiation of mRNA translation by binding to the m7G cap of mRNA targets, thus likely precluding the recruitment of eIF4E.