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      AGO-RBP crosstalk on target mRNAs: Implications in miRNA-guided gene silencing and cancer

      review-article
      Translational Oncology
      Neoplasia Press
      miRNAs, Argonaute protein, RBPs, mRNAs, miRISC, Cancer

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          Highlights

          • mRNA 3′ UTRs facilitate an intricate network of interactions between miRNA-AGO and RBPs.

          • The mode of interaction between miRNA-AGO and RBPs on target mRNAs determine the outcome of gene regulation in cancer.

          • RBP-RBP interactions and their cumulative binding patterns on mRNA 3′ UTRs influence miRNA-AGO recognition of targets for repression.

          • Transcriptome wide approaches exploring AGO-RBP interactions in primary tumors is paramount to have a comprehensive understanding of mRNA metabolism in cancer.

          Abstract

          MicroRNAs (miRNAs) and RNA-binding proteins (RBPs) are important regulators of mRNA translation and stability in eukaryotes. While miRNAs can only bind their target mRNAs in association with Argonaute proteins (AGOs), RBPs directly bind their targets either as single entities or in complex with other RBPs to control mRNA metabolism. miRNA binding in 3′ untranslated regions (3′ UTRs) of mRNAs facilitates an intricate network of interactions between miRNA-AGO and RBPs, thus determining the fate of overlapping targets. Here, we review the current knowledge on the interplay between miRNA-AGO and multiple RBPs in different cellular contexts, the rules underlying their synergism and antagonism on target mRNAs, as well as highlight the implications of these regulatory modules in cancer initiation and progression.

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          Most cited references126

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          Metazoan MicroRNAs

          MicroRNAs (miRNAs) are ∼22 nt RNAs that direct posttranscriptional repression of mRNA targets in diverse eukaryotic lineages. In humans and other mammals, these small RNAs help sculpt the expression of most mRNAs. This article reviews advances in our understanding of the defining features of metazoan miRNAs and their biogenesis, genomics, and evolution. It then reviews how metazoan miRNAs are regulated, how they recognize and cause repression of their targets, and the biological functions of this repression, with a compilation of knockout phenotypes that shows that important biological functions have been identified for most of the broadly conserved miRNAs of mammals.
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            Most mammalian mRNAs are conserved targets of microRNAs.

            MicroRNAs (miRNAs) are small endogenous RNAs that pair to sites in mRNAs to direct post-transcriptional repression. Many sites that match the miRNA seed (nucleotides 2-7), particularly those in 3' untranslated regions (3'UTRs), are preferentially conserved. Here, we overhauled our tool for finding preferential conservation of sequence motifs and applied it to the analysis of human 3'UTRs, increasing by nearly threefold the detected number of preferentially conserved miRNA target sites. The new tool more efficiently incorporates new genomes and more completely controls for background conservation by accounting for mutational biases, dinucleotide conservation rates, and the conservation rates of individual UTRs. The improved background model enabled preferential conservation of a new site type, the "offset 6mer," to be detected. In total, >45,000 miRNA target sites within human 3'UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. Mammalian-specific miRNAs have far fewer conserved targets than do the more broadly conserved miRNAs, even when considering only more recently emerged targets. Although pairing to the 3' end of miRNAs can compensate for seed mismatches, this class of sites constitutes less than 2% of all preferentially conserved sites detected. The new tool enables statistically powerful analysis of individual miRNA target sites, with the probability of preferentially conserved targeting (P(CT)) correlating with experimental measurements of repression. Our expanded set of target predictions (including conserved 3'-compensatory sites), are available at the TargetScan website, which displays the P(CT) for each site and each predicted target.
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              Regulation of microRNA function in animals

              Since their serendipitous discovery in nematodes, microRNAs (miRNAs) have emerged as key regulators of biological processes in animals. These small RNAs form complex regulatory networks in cell development, differentiation and homeostasis. Deregulation of miRNA function is associated with an increasing number of human diseases, particularly cancer. Recent discoveries have expanded our understanding of how miRNAs are regulated. Here we review the mechanisms that modulate miRNA activity, their stability and their localization through alternative processing, sequence editing, post-translational modifications of Argonaute proteins, viral factors, transport from the cytoplasm and regulation of miRNA–target interactions. We conclude by discussing intriguing open questions to be answered by future research.
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                Author and article information

                Contributors
                Journal
                Transl Oncol
                Transl Oncol
                Translational Oncology
                Neoplasia Press
                1936-5233
                26 April 2022
                July 2022
                26 April 2022
                : 21
                : 101434
                Affiliations
                [0001]Department of Biochemistry, Memorial University of Newfoundland, 45 Arctic Avenue, St. John's, NL A1C 5S7, Canada
                Article
                S1936-5233(22)00093-6 101434
                10.1016/j.tranon.2022.101434
                9136600
                35477066
                0ccf6d6c-3f3c-4c8e-9da6-4f5889922318
                © 2022 The Authors. Published by Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 10 April 2022
                : 12 April 2022
                Categories
                Review

                mirnas,argonaute protein,rbps,mrnas,mirisc,cancer
                mirnas, argonaute protein, rbps, mrnas, mirisc, cancer

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