Epitranscriptome and FMRP Regulated mRNA Translation
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Abstract:
An important regulatory mechanism affecting mRNA translation involves various covalent modifications of RNA, which establish distinct epitranscriptomic signatures that actively influence various physiological processes. Dendritic translation in mammalian neurons is a potent target for RNA modification-based regulation. In this mini-review, we focus on the effect of potential RNA modifications on the spatiotemporal regulation of the dendritic translation of mRNAs, which are targeted by two important neuronal translational co-regulators, namely TDP-43 and Fragile X Mental Retardation Protein (FMRP).Keywords:
Translational regulation
Eukaryotic translation
The restricted spatiotemporal translation of maternal mRNAs, which is crucial for correct cell fate specification in early C. elegans embryos, is regulated primarily through the 3'UTR. Although genetic screens have identified many maternally expressed cell fate-controlling RNA-binding proteins (RBPs), their in vivo targets and the mechanism(s) by which they regulate these targets are less clear. These RBPs are translated in oocytes and localize to one or a few blastomeres in a spatially and temporally dynamic fashion unique for each protein and each blastomere. Here, we characterize the translational regulation of maternally supplied mom-2 mRNA, which encodes a Wnt ligand essential for two separate cell-cell interactions in early embryos. A GFP reporter that includes only the mom-2 3'UTR is translationally repressed properly in oocytes and early embryos, and then correctly translated only in the known Wnt signaling cells. We show that the spatiotemporal translation pattern of this reporter is regulated combinatorially by a set of nine maternally supplied RBPs. These nine proteins all directly bind the mom-2 3'UTR in vitro and function as positive or negative regulators of mom-2 translation in vivo. The net translational readout for the mom-2 3'UTR reporter is determined by competitive binding between positive- and negative-acting RBPs for the 3'UTR, along with the distinct spatiotemporal localization patterns of these regulators. We propose that the 3'UTR of maternal mRNAs contains a combinatorial code that determines the topography of associated RBPs, integrating positive and negative translational inputs.
Translational regulation
Cell fate determination
Translational efficiency
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Translational regulation plays an essential role in many phases of the Drosophila life cycle. During embryogenesis, specification of the developing body pattern requires co-ordination of the translation of oskar, gurken and nanos mRNAs with their subcellular localization. In addition, dosage compensation is controlled by Sex-lethal-mediated translational regulation while dFMR1 (the Drosophila homologue of the fragile X mental retardation protein) controls translation of various mRNAs which function in the nervous system. Here we describe some of the mechanisms that are utilized to regulate these various processes. Our review highlights the complexity that can be involved with multiple factors employing different mechanisms to control the translation of a single mRNA.
Translational regulation
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Abstract Although some circular RNAs (circRNAs) were found to be translated through IRES-driven mechanism, the scope and functions of circRNA translation are unclear because endogenous IRESs are rare. To determine the prevalence and mechanism of circRNA translation, we developed a cell-based system to screen random sequences and identified 97 overrepresented hexamers that drive cap-independent circRNA translation. These IRES-like short elements are significantly enriched in endogenous circRNAs and sufficient to drive circRNA translation. We further identified multiple trans -acting factors that bind these IRES-like elements to initiate translation. Using mass-spectrometry data, hundreds of circRNA-coded peptides were identified, most of which have low abundance due to rapid degradation. As judged by mass-spectrometry, 50% of translatable endogenous circRNAs undergo rolling circle translation, several of which were experimentally validated. Consistently, mutations of the IRES-like element in one circRNA reduced its translation. Collectively, our findings suggest a pervasive translation of circRNAs, providing profound implications in translation control.
Eukaryotic translation
Circular RNA
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Translational regulation
Translational efficiency
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Abstract Some circular RNAs (circRNAs) were found to be translated through IRES-driven mechanism, however the scope and functions of circRNA translation are unclear because endogenous IRESs are rare. To determine the prevalence and mechanism of circRNA translation, we develop a cell-based system to screen random sequences and identify 97 overrepresented hexamers that drive cap-independent circRNA translation. These IRES-like short elements are significantly enriched in endogenous circRNAs and sufficient to drive circRNA translation. We further identify multiple trans -acting factors that bind these IRES-like elements to initiate translation. Using mass-spectrometry data, hundreds of circRNA-coded peptides are identified, most of which have low abundance due to rapid degradation. As judged by mass-spectrometry, 50% of translatable endogenous circRNAs undergo rolling circle translation, several of which are experimentally validated. Consistently, mutations of the IRES-like element in one circRNA reduce its translation. Collectively, our findings suggest a pervasive translation of circRNAs, providing profound implications in translation control.
Eukaryotic translation
Circular RNA
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Translation of proteins by the ribosome represents the endpoint of gene expression and is highly regulated. The structures of ribosomal complexes represent a triumph of structural biology. Yet these structures lack a time axis: dynamic measurements are needed to understand the mysteries of translation. Here we present our broad efforts to develop and use single‐molecule fluorescence methods to track translation in real time. Using fluorescent labels on transfer RNAs, factors, mRNAs and ribosomal subunits, we have mapped conformational and compositional dynamics of the translational machinery during protein synthesis. Our focus has recently been on the dynamics of initiation, by which translational reading frame is established.
Translational regulation
Translational frameshift
Dynamics
Eukaryotic translation
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An important regulatory mechanism affecting mRNA translation involves various covalent modifications of RNA, which establish distinct epitranscriptomic signatures that actively influence various physiological processes. Dendritic translation in mammalian neurons is a potent target for RNA modification-based regulation. In this mini-review, we focus on the effect of potential RNA modifications on the spatiotemporal regulation of the dendritic translation of mRNAs, which are targeted by two important neuronal translational co-regulators, namely TDP-43 and Fragile X Mental Retardation Protein (FMRP).
Translational regulation
Eukaryotic translation
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A disrupted cell is capable of synthesizing protein from amino acids depending upon the template RNA. This discovery, half a century ago, set the stage for biochemical studies on the gene expression process occurring in cells. The cell-free translation system successfully revealed the function of a number of key molecules participating in the translation system, such as ribosome, mRNA, tRNA, and protein factors and, moreover, elucidated the very complicated mechanism of protein synthesis. Although still frequently utilized in these experimental studies, cell-free translation is beginning to make a mark as an attractive tool for protein production as a potential alternative to an in vivo expression system. Moreover, the cell-free translation system is prospective as a method for the synthesis of protein with unnatural amino acids and for the selection of genotypes from peptide libraries.
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Translation system
Ribosome profiling
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Translational regulation
Eukaryotic translation
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The lambda cI lysogenic transcript is unusual in having no leader. Expression of a cI-lacZ protein fusion was relatively resistant to kasugamycin and pactamycin, which inhibit translation initiation on transcripts with leaders. Our data imply that there are distinct differences in translation initiation between the two classes of transcripts.
Lysogenic cycle
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