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      A structural view of microRNA–target recognition

      research-article
      1 , 1 , 2 , *
      Nucleic Acids Research
      Oxford University Press

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          Abstract

          It is well established that the correct identification of the messenger RNA targeted by a given microRNA (miRNA) is a difficult problem, and that available methods all suffer from low specificity. We hypothesize that the correct identification of the pairing should take into account the effect of the Argonaute protein (AGO), an essential catalyst of the recognition process. Therefore, we developed a strategy named MiREN for building and scoring three-dimensional models of the ternary complex formed by AGO, a miRNA and 22 nt of a target mRNA that putatively interacts with it. We show here that MiREN can be used to assess the likelihood that an RNA molecule is the target of a given miRNA and that this approach is more accurate than other existing methods, usually based on sequence or sequence-related features. Our results also suggest that AGO plays a relevant role in the selection of the miRNA targets. Our method can represent an additional step for refining predictions made by faster but less accurate classical methods for the identification of miRNA targets.

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          Most cited references20

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          Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites

          mirSVR is a new machine learning method for ranking microRNA target sites by a down-regulation score. The algorithm trains a regression model on sequence and contextual features extracted from miRanda-predicted target sites. In a large-scale evaluation, miRanda-mirSVR is competitive with other target prediction methods in identifying target genes and predicting the extent of their downregulation at the mRNA or protein levels. Importantly, the method identifies a significant number of experimentally determined non-canonical and non-conserved sites.
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            Ago HITS-CLIP decodes miRNA-mRNA interaction maps

            Summary MicroRNAs (miRNAs) play critical roles in the regulation of gene expression. However, since miRNA activity requires base pairing with only 6-8 nucleotides of mRNA, predicting target mRNAs is a major challenge. Recently, high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) has identified functional protein-RNA interaction sites. Here we use HITS-CLIP to covalently crosslink native Argonaute (Ago) protein-RNA complexes in mouse brain. This produced two simultaneous datasets—Ago-miRNA and Ago-mRNA binding sites—that were combined with bioinformatic analysis to identify miRNA-target mRNA interaction sites. We validated genome-wide interaction maps for miR-124, and generated additional maps for the 20 most abundant miRNAs present in P13 mouse brain. Ago HITS-CLIP provides a general platform for exploring the specificity and range of miRNA action in vivo, and identifies precise sequences for targeting clinically relevant miRNA-mRNA interactions.
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              The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC.

              Since their discovery almost two decades ago, microRNAs (miRNAs) have been shown to function by post-transcriptionally regulating protein accumulation. Understanding how miRNAs silence targeted mRNAs has been the focus of intensive research. Multiple models have been proposed, with few mechanistic details having been worked out. However, the past few years have witnessed a quantum leap forward in our understanding of the molecular mechanics of miRNA-mediated gene silencing. In this review we describe recent discoveries, with an emphasis on how miRISC post-transcriptionally controls gene expression by inhibiting translation and/or initiating mRNA decay, and how trans-acting factors control miRNA action.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                19 May 2016
                28 January 2016
                28 January 2016
                : 44
                : 9
                : e82
                Affiliations
                [1 ]Department of Physics, Sapienza University, Piazzale Aldo Moro, 5-00184 Rome, Italy
                [2 ]Istituto Pasteur-Fondazione Cenci Bolognetti, Viale Regina Elena 291, 00161 Rome, Italy
                Author notes
                [* ]To whom correspondence should be addressed. Tel: +39 064 991 4550; Fax: +39 064 957 697; Email: Anna.tramontano@ 123456uniroma1.it
                Article
                10.1093/nar/gkw043
                4872079
                26825463
                f815781f-cc7b-4d31-b9ec-10da9156d6bb
                © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                : 14 January 2016
                : 11 December 2015
                : 26 September 2015
                Page count
                Pages: 8
                Categories
                16
                24
                Methods Online
                Custom metadata
                19 May 2016

                Genetics
                Genetics

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