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Regulatory effects of cotranscriptional RNA structure formation and transitions

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RNAs, which play significant roles in many fundamental biological processes of life, fold into sophisticated and precise structures. RNA folding is a dynamic and intricate process, which conformation transition of coding and noncoding RNAs form the primary elements of genetic regulation. The cellular environment contains various intrinsic and extrinsic factors that potentially affect RNA folding in vivo, and experimental and theoretical evidence increasingly indicates that the highly flexible features of the RNA structure are affected by these factors, which include the flanking sequence context, physiochemical conditions, cis RNA–RNA interactions, and RNA interactions with other molecules. Furthermore, distinct RNA structures have been identified that govern almost all steps of biological processes in cells, including transcriptional activation and termination, transcriptional mutagenesis, 5′‐capping, splicing, 3′‐polyadenylation, mRNA export and localization, and translation. Here, we briefly summarize the dynamic and complex features of RNA folding along with a wide variety of intrinsic and extrinsic factors that affect RNA folding. We then provide several examples to elaborate RNA structure‐mediated regulation at the transcriptional and posttranscriptional levels. Finally, we illustrate the regulatory roles of RNA structure and discuss advances pertaining to RNA structure in plants. WIREs RNA 2016, 7:562–574. doi: 10.1002/wrna.1350 This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
Factors for RNA structural formation and transition in vivo.
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Regulatory effect for posttranscriptional processes of RNA structural transition. (a) The mechanism of RNA being exported from nucleus to cytoplasm depend on whether RNA folded correct or not. Misfolded RNAs are unsuccessfully exported, while native RNAs can be exported from nucleus to cytoplasm through correct processing. (b) The protein‐dependent RNA structure transition in the 3′‐UTR of VEGFA mRNA regulates its translation. Strong and weak RNase cleavage sites are marked by yellow and green circles, respectively. Mutually conformation transition can be occurred between the translation‐permissive (TP) conformer and translation‐silencing (TS) conformer. VEGFA expression was blocked by interferon‐γ (IFN‐γ) binding to the IFN‐γ‐activated inhibitor of translation (GAIT) complex to form TS conformer, while hypoxic stress that leads to hnRNPL binding and causes a switch to a TP conformer.
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The regulation for mRNA transcriptional and posttranscriptional processing of cotranscriptional RNA structures formation. (a) The cotranscriptional process of 5′‐capping of flavivirus RNA. The type 1 cap is formed sense strand RNA through four sequential enzyme activities: triphosphatase activity releases the terminal phosphate from the 5′‐triphosphate end of sense strand RNA; a guanosine monophosphate (GMP) is transferred to the 5′ end of dephosphorylated RNA via guanylytransferase activity; subsequently, the capped RNA is methylated first at the N7 position of the guanine cap and then at the ribose 2′‐O position of the first RNA. The MTase domain of Guanine‐N7‐methyltransferase carries out both methylations using S‐adenosyl‐l‐methionine (SAM) as a methyl donor and SAM is converted to S‐adenosyl‐l‐homosysteine (SAH). (b) The cotranscriptional process of 3′ polyadenylation of RNA involving in mRNA stability in yeast. In this model, four isoforms were demonstrated and one isoform is readily degraded by the exosome complex (Pab1, purple) due to the absence of stability element. In contrast, another isoform possesses a longer half‐life due to the presence of a stability element, which the presence of either a polyU‐poly(A) tail or a stem‐loop near the 3′ terminus blocks exosome‐dependent degradation. (c) The intron's self‐excision of the ribozyme riboswitch. In the absence of c‐di‐GMP, the intron take advantage of GTP2 cleavage site, thus yielding truncated RNAs that are not expressed. Binding to c‐di‐GMP to the riboswitch in the presence of GTP promotes cleavage site 1 (GTP1) and self‐excision of the group I self‐splicing intron, leading to mRNA is efficiently translated.
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Regulatory effect for cotranscriptional processes of RNA structures formation. (a) The cotranscriptional RNA folding pathways is modulated by adenine riboswitch. Transcription termination resulting from ligand binding to the aptamer domain of the adenine riboswitch and subsequent stabilization of a terminator stem‐loop and exposure of a poly‐(U) stretch. (b) The cotranscriptional mutagenesis is modulated by RNA folding and R‐loop formation. With weak RNA folding, an R‐loop accumulated resulting in the exposure time of the naked nontemplate DNA and error‐prone DNA synthesis increased, further leading to a higher mutation rate. By comparison, the R‐loop is dissolved when RNA folding stronger, resulting in the exposure time of the naked nontemplate DNA and error‐prone DNA synthesis is reduced and subsequent a lower mutation rate.
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Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry

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