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Metabolite sensing in eukaryotic mRNA biology

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All living creatures change their gene expression program in response to nutrient availability and metabolic demands. Nutrients and metabolites can directly control transcription and activate second‐messenger systems. More recent studies reveal that metabolites also affect post‐transcriptional regulatory mechanisms. Here, we review the increasing number of connections between metabolism and post‐transcriptional regulation in eukaryotic organisms. First, we present evidence that riboswitches, a common mechanism of metabolite sensing in bacteria, also function in eukaryotes. Next, we review an example of a double stranded RNA modifying enzyme that directly interacts with a metabolite, suggesting a link between RNA editing and metabolic state. Finally, we discuss work that shows some metabolic enzymes bind directly to RNA to affect mRNA stability or translation efficiency. These examples were discovered through gene‐specific genetic, biochemical, and structural studies. A directed systems level approach will be necessary to determine whether they are anomalies of evolution or pioneer discoveries in what may be a broadly connected network of metabolism and post‐transcriptional regulation. WIREs RNA 2013, 4:387–396. doi: 10.1002/wrna.1167 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications Regulatory RNAs/RNAi/Riboswitches > Riboswitches

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The structure of human ADAR2 bound to IP6. (a) The surface of hADAR2 is rendered in mesh, revealing the deep internal cavity that coordinates IP6 (rendered in spheres). The structure was rendered from coordinate file 1ZY7. (b) Chemical structure of IP6, sensed by ADAR.
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TPP‐regulated alternative splicing of the NMT1 gene. (a) Schematic of the 5′ UTR intron structure. The thin line above the schematic denotes the predominant isoform in low TPP conditions. The thick line below the schematic denotes the pattern in high TPP conditions. (b) The low TPP isoform contains a short 5′ UTR with a single initiation codon, leading to efficient translation of NMT1. (c) The high TPP isoform contains a longer 5′ UTR with two uORFs, leading to reduced translation initiation of the cognate NMT1 ORF. (d) Chemical structure of TPP, sensed by the riboswitch motif in the 5′ UTR intron.
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The two forms of IRP1. (a) structure of IRP1 in the iron replete state adopts the canonical aconite fold. The protein structure is rendered as a cartoon, the 4Fe‐FS cluster is rendered as spheres. The structure was rendered form coordinate file 2B3X. (b) In iron deficient state, IRP1 adopts an alternative conformation that binds to a specific stem loop RNA structure (red). The structure was rendered from coordinate file 3SNP. (c) Chemical structure of the 4Fe‐4S cluster sensed by IRP1.
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Regulatory RNAs/RNAi/Riboswitches > Riboswitches
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions
RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition

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