microRNAs是一種長21－25nt的單鏈小分子RNA，由于其在細(xì)胞生長和發(fā)育過程的調(diào)節(jié)作用而倍受科學(xué)家們的矚目,。近期來自英國和美國的科學(xué)家在這一小分子研究方面又獲得重要進(jìn)展,，值得關(guān)注。
對于miRNAs的研究起始于時序調(diào)控小RNA（stRNAs）,，由于miRNAs在物種進(jìn)化中相當(dāng)保守,，在植物、動物和真菌中發(fā)現(xiàn)的miRNAs只在特定的組織和發(fā)育階段表達(dá),，而且這種特異性和時序性,，決定了組織和細(xì)胞的功能特異性，表明miRNA在細(xì)胞生長和發(fā)育過程的調(diào)節(jié)過程中起多種作用,，因此miRNA的研究受到了生物學(xué)家的廣泛關(guān)注,。
siRNAs（Short interfering RNAs）相似于miRNAs，也是通過Dicer產(chǎn)生,，但是其前體是完整的雙鏈RNA,。siRNAs能調(diào)控轉(zhuǎn)錄后修飾，以及表觀基因組修飾,，不同的真核生物,，比如真菌，植物,，原生動物和后生動物都能產(chǎn)生siRNAs,，但是至今為止,，在單細(xì)胞生物體中并未發(fā)現(xiàn)miRNAs，這讓科學(xué)家們認(rèn)為miRNAs是在進(jìn)化上植物和動物多細(xì)胞生命形態(tài)出現(xiàn)之后才存在的,。
在Nature的這篇文章中，來自英國John Innes中心（John Innes Centre）,，東英格蘭大學(xué)（University of East Anglia）的研究人員發(fā)現(xiàn)單細(xì)胞藻類：萊茵衣藻（Chlamydomonas reinhardtii）包含有miRNAs,，miRNAs假設(shè)的進(jìn)化上前體，以及與高等植物類似的siRNAs——萊茵衣藻是一種單細(xì)胞真核鞭毛藻類,，是研究多種生命活動（如光合作用,、鞭毛組裝、趨光性和生理節(jié)律等）的模式生物,，與酵母細(xì)胞有許多共同的特征,，素有“光合酵母”之稱。
從這一研究中可以看出,，藻類和高等植物中的miRNAs和siRNAs共同特點說明復(fù)雜RNA沉默系統(tǒng)在多細(xì)胞生命形態(tài)出現(xiàn)之前就存在了,，是一種原始真核細(xì)胞的特征。
原始出處：
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: [email protected]).
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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另一篇有關(guān)miRNAs的研究新進(jìn)展則是圍繞Argonaute蛋白展開,，這篇發(fā)表在Cell網(wǎng)絡(luò)版上的文章由美國賓州大學(xué)醫(yī)學(xué)院醫(yī)學(xué)系和病理學(xué)系的研究人員完成,。
Argonaute（Ago）蛋白是一個高度保守的家族，這一蛋白家族包括許多成員,，它們組成了RNA誘導(dǎo)的沉默復(fù)合體的核心元件,，是RNA干擾所必須的——Argonaute蛋白選擇性地與miRNA和siRNA結(jié)合，并與Dicer酶相互作用,，其PIWI盒子與Dicer的RNaseⅢ結(jié)構(gòu)域直接相互作用,，PIWI與Dicer之間的相互作用可能會促進(jìn)miRNA/siRNA的釋放。
人類let-7miRNA以依賴于m7G cap的方式抑制mRNA靶標(biāo)的翻譯啟動,，以及蛋白的表達(dá),，但是其中的分子機制，以及其中Ago在翻譯調(diào)控過程的作用至今并不清楚,。
在這篇文章中,，研究人員在Ago蛋白中間區(qū)域發(fā)現(xiàn)了一個motif（MC），這個結(jié)構(gòu)區(qū)域與eIF4E（翻譯啟動必需因子）的m7G帽結(jié)合結(jié)構(gòu)域十分相似,，而且他們也在人類Ago2的MC結(jié)構(gòu)上發(fā)現(xiàn)了保守的芳香族殘基,，這對于綁定到m7G帽和翻譯抑制是必需的，但是并不影響Ago與miRNA的組裝或者Ago2的活性,。因此研究認(rèn)為Ago2通過結(jié)合到mRAN靶標(biāo)m7G結(jié)構(gòu)上來抑制mRNA的翻譯,，而排除了eIF4E重新募集的可能性。
原始出處：
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
[email protected]
Corresponding author
Zissimos Mourelatos
[email protected]
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.
