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Molecules (Basel, Switzerland) Jul 2017Riboswitches are genetic control elements within non-coding regions of mRNA. These self-regulatory elements have been found to sense a range of small metabolites, ions,... (Review)
Review
Riboswitches are genetic control elements within non-coding regions of mRNA. These self-regulatory elements have been found to sense a range of small metabolites, ions, and other physical signals to exert regulatory control of transcription, translation, and splicing. To date, more than a dozen riboswitch classes have been characterized that vary widely in size and secondary structure. Extensive experiments and theoretical studies have made great strides in understanding the general structures, genetic mechanisms, and regulatory activities of individual riboswitches. As the ligand-dependent co-transcriptional folding and unfolding dynamics of riboswitches are the key determinant of gene expression, it is important to investigate the thermodynamics and kinetics of riboswitches both in the presence and absence of metabolites under the transcription. This review will provide a brief summary of the studies about the regulation mechanisms of the , S, , and riboswitches based on the ligand-dependent co-transcriptional folding of the riboswitches.
Topics: Gene Expression Regulation; Kinetics; Ligands; Nucleic Acid Conformation; RNA Folding; RNA, Messenger; Riboswitch; Thermodynamics; Transcription, Genetic
PubMed: 28703767
DOI: 10.3390/molecules22071169 -
Transcription Aug 2021To exert their functions, RNAs adopt diverse structures, ranging from simple secondary to complex tertiary and quaternary folds. , RNA folding starts with RNA...
To exert their functions, RNAs adopt diverse structures, ranging from simple secondary to complex tertiary and quaternary folds. , RNA folding starts with RNA transcription, and a wide variety of processes are coupled to co-transcriptional RNA folding events, including the regulation of fundamental transcription dynamics, gene regulation by mechanisms like attenuation, RNA processing or ribonucleoprotein particle formation. While co-transcriptional RNA folding and associated co-transcriptional processes are by now well accepted as pervasive regulatory principles in all organisms, investigations into the role of the transcription machinery in co-transcriptional folding processes have so far largely focused on effects of the order in which RNA regions are produced and of transcription kinetics. Recent structural and structure-guided functional analyses of bacterial transcription complexes increasingly point to an additional role of RNA polymerase and associated transcription factors in supporting co-transcriptional RNA folding by fostering or preventing strategic contacts to the nascent transcripts. In general, the results support the view that transcription complexes can act as RNA chaperones, a function that has been suggested over 30 years ago. Here, we discuss transcription complexes as RNA chaperones based on recent examples from bacterial transcription.
Topics: DNA-Directed RNA Polymerases; Nucleic Acid Conformation; RNA; RNA Folding; RNA Processing, Post-Transcriptional; Transcription, Genetic
PubMed: 34719334
DOI: 10.1080/21541264.2021.1985931 -
Nucleic Acids Research Nov 2018Viroids were described 47 years ago as the smallest RNA molecules capable of infecting plants and autonomously self-replicating without an encoded protein. Work on... (Review)
Review
Viroids were described 47 years ago as the smallest RNA molecules capable of infecting plants and autonomously self-replicating without an encoded protein. Work on viroids initiated the development of a number of innovative methods. Novel chromatographic and gelelectrophoretic methods were developed for the purification and characterization of viroids; these methods were later used in molecular biology, gene technology and in prion research. Theoretical and experimental studies of RNA folding demonstrated the general biological importance of metastable structures, and nuclear magnetic resonance spectroscopy of viroid RNA showed the partially covalent nature of hydrogen bonds in biological macromolecules. RNA biochemistry and molecular biology profited from viroid research, such as in the detection of RNA as template of DNA-dependent polymerases and in mechanisms of gene silencing. Viroids, the first circular RNA detected in nature, are important for studies on the much wider spectrum of circular RNAs and other non-coding RNAs.
Topics: Hydrogen Bonding; Plant Diseases; Plants; Plasmids; Prions; RNA; RNA Folding; RNA Interference; RNA, Catalytic; RNA, Circular; RNA, Viral; Temperature; Viroids
PubMed: 30304486
DOI: 10.1093/nar/gky903 -
Briefings in Bioinformatics Nov 2023RNA biology has risen to prominence after a remarkable discovery of diverse functions of noncoding RNA (ncRNA). Most untranslated transcripts often exert their... (Review)
Review
RNA biology has risen to prominence after a remarkable discovery of diverse functions of noncoding RNA (ncRNA). Most untranslated transcripts often exert their regulatory functions into RNA-RNA complexes via base pairing with complementary sequences in other RNAs. An interplay between RNAs is essential, as it possesses various functional roles in human cells, including genetic translation, RNA splicing, editing, ribosomal RNA maturation, RNA degradation and the regulation of metabolic pathways/riboswitches. Moreover, the pervasive transcription of the human genome allows for the discovery of novel genomic functions via RNA interactome investigation. The advancement of experimental procedures has resulted in an explosion of documented data, necessitating the development of efficient and precise computational tools and algorithms. This review provides an extensive update on RNA-RNA interaction (RRI) analysis via thermodynamic- and comparative-based RNA secondary structure prediction (RSP) and RNA-RNA interaction prediction (RIP) tools and their general functions. We also highlighted the current knowledge of RRIs and the limitations of RNA interactome mapping via experimental data. Then, the gap between RSP and RIP, the importance of RNA homologues, the relationship between pseudoknots, and RNA folding thermodynamics are discussed. It is hoped that these emerging prediction tools will deepen the understanding of RNA-associated interactions in human diseases and hasten treatment processes.
Topics: Humans; RNA; Computational Biology; RNA, Untranslated; Genomics; RNA Folding; Nucleic Acid Conformation; Algorithms
PubMed: 38040490
DOI: 10.1093/bib/bbad421 -
RNA (New York, N.Y.) Dec 2018The revolution in sequencing technology demands new tools to interpret the genetic code. As in vivo transcriptome-wide chemical probing techniques advance, new... (Review)
Review
The revolution in sequencing technology demands new tools to interpret the genetic code. As in vivo transcriptome-wide chemical probing techniques advance, new challenges emerge in the RNA folding problem. The emphasis on one sequence folding into a single minimum free energy structure is fading as a new focus develops on generating RNA structural ensembles and identifying functional structural features in ensembles. This review describes an efficient combinatorially complete method and three free energy minimization approaches to predicting RNA structures with more than one functional fold, as well as two methods for analysis of a thermodynamics-based Boltzmann ensemble of structures. The review then highlights two examples of viral RNA 3'-UTR regions that fold into more than one conformation and have been characterized by single molecule fluorescence energy resonance transfer or NMR spectroscopy. These examples highlight the different approaches and challenges in predicting structure and function from sequence for RNA with multiple biological roles and folds. More well-defined examples and new metrics for measuring differences in RNA structures will guide future improvements in prediction of RNA structure and function from sequence.
Topics: Algorithms; Computational Biology; Nucleic Acid Conformation; RNA; RNA Folding; RNA, Viral; Software; Thermodynamics
PubMed: 30143552
DOI: 10.1261/rna.067827.118 -
BioEssays : News and Reviews in... Aug 2022Construction of the eukaryotic ribosome is a complex process in which a nascent ribosomal RNA (rRNA) emerging from RNA Polymerase I hierarchically folds into a native...
Construction of the eukaryotic ribosome is a complex process in which a nascent ribosomal RNA (rRNA) emerging from RNA Polymerase I hierarchically folds into a native three-dimensional structure. Modular assembly of individual RNA domains through interactions with ribosomal proteins and a myriad of assembly factors permit efficient disentanglement of the error-prone RNA folding process. Following these dynamic events, long-range tertiary interactions are orchestrated to compact rRNA. A combination of genetic, biochemical, and structural studies is now providing clues into how a nascent rRNA is transformed into a functional ribosome with high precision. With this essay, we aim to draw attention to the poorly understood process of establishing correct RNA tertiary contacts during ribosome formation.
Topics: RNA Folding; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 35751450
DOI: 10.1002/bies.202200066 -
Journal of Molecular Biology Oct 2016Structured RNAs fold through multiple pathways, but we have little understanding of the molecular features that dictate folding pathways and determine rates along a...
Structured RNAs fold through multiple pathways, but we have little understanding of the molecular features that dictate folding pathways and determine rates along a given pathway. Here, we asked whether folding of a complex RNA can be understood from its structural modules. In a two-piece version of the Tetrahymena group I ribozyme, the separated P5abc subdomain folds to local native secondary and tertiary structure in a linked transition and assembles with the ribozyme core via three tertiary contacts: a kissing loop (P14), a metal core-receptor interaction, and a tetraloop-receptor interaction, the first two of which are expected to depend on native P5abc structure from the local transition. Native gel, NMR, and chemical footprinting experiments showed that mutations that destabilize the native P5abc structure slowed assembly up to 100-fold, indicating that P5abc folds first and then assembles with the core by conformational selection. However, rate decreases beyond 100-fold were not observed because an alternative pathway becomes dominant, with nonnative P5abc binding the core and then undergoing an induced-fit rearrangement. P14 is formed in the rate-limiting step along the conformational selection pathway but after the rate-limiting step along the induced-fit pathway. Strikingly, the assembly rate along the conformational selection pathway resembles that of an isolated kissing loop similar to P14, and the rate along the induced-fit pathway resembles that of an isolated tetraloop-receptor interaction. Our results indicate substantial modularity in RNA folding and assembly and suggest that these processes can be understood in terms of underlying structural modules.
Topics: DNA Mutational Analysis; Electrophoresis, Polyacrylamide Gel; Magnetic Resonance Spectroscopy; Nucleic Acid Conformation; RNA Folding; RNA, Catalytic; Tetrahymena
PubMed: 27452365
DOI: 10.1016/j.jmb.2016.07.013 -
Nature Communications Nov 2023T-box riboswitches are unique riboregulators where gene regulation is mediated through interactions between two highly structured RNAs. Despite extensive structural...
T-box riboswitches are unique riboregulators where gene regulation is mediated through interactions between two highly structured RNAs. Despite extensive structural insights, how RNA-RNA interactions drive the folding and structural transitions of T-box to achieve functional conformations remains unclear. Here, by combining SAXS, single-molecule FRET and computational modeling, we elaborate the folding energy landscape of a translational T-box aptamer consisting of stems I, II and IIA/B, which Mg-induced global folding and tRNA binding are cooperatively coupled. smFRET measurements reveal that high Mg stabilizes IIA/B and its stacking on II, which drives the pre-docking of I and II into a competent conformation, subsequent tRNA binding promotes docking of I and II to form a high-affinity tRNA binding groove, of which the essentiality of IIA/B and S-turn in II is substantiated with mutational analysis. We highlight a delicate balance among Mg, the intra- and intermolecular RNA-RNA interactions in modulating RNA folding and function.
Topics: Riboswitch; Nucleic Acid Conformation; Scattering, Small Angle; X-Ray Diffraction; RNA, Transfer; RNA Folding; RNA
PubMed: 37968328
DOI: 10.1038/s41467-023-43232-z -
Nature Communications Jan 2023Guanine (G)-rich nucleic acids can fold into G-quadruplex (G4) structures under permissive conditions. Although many RNAs contain sequences that fold into RNA G4s (rG4s)...
Guanine (G)-rich nucleic acids can fold into G-quadruplex (G4) structures under permissive conditions. Although many RNAs contain sequences that fold into RNA G4s (rG4s) in vitro, their folding and functions in vivo are not well understood. In this report, we showed that the folding of putative rG4s in human cells into rG4 structures is dynamically regulated under stress. By using high-throughput dimethylsulfate (DMS) probing, we identified hundreds of endogenous stress-induced rG4s, and validated them by using an rG4 pull-down approach. Our results demonstrate that stress-induced rG4s are enriched in mRNA 3'-untranslated regions and enhance mRNA stability. Furthermore, stress-induced rG4 folding is readily reversible upon stress removal. In summary, our study revealed the dynamic regulation of rG4 folding in human cells and suggested that widespread rG4 motifs may have a global regulatory impact on mRNA stability and cellular stress response.
Topics: Humans; RNA; RNA, Messenger; G-Quadruplexes; RNA Folding; RNA Stability
PubMed: 36639366
DOI: 10.1038/s41467-023-35811-x -
Nature Reviews. Molecular Cell Biology Aug 2019RNAs fold into 3D structures that range from simple helical elements to complex tertiary structures and quaternary ribonucleoprotein assemblies. The functions of many... (Review)
Review
RNAs fold into 3D structures that range from simple helical elements to complex tertiary structures and quaternary ribonucleoprotein assemblies. The functions of many regulatory RNAs depend on how their 3D structure changes in response to a diverse array of cellular conditions. In this Review, we examine how the structural characterization of RNA as dynamic ensembles of conformations, which form with different probabilities and at different timescales, is improving our understanding of RNA function in cells. We discuss the mechanisms of gene regulation by microRNAs, riboswitches, ribozymes, post-transcriptional RNA modifications and RNA-binding proteins, and how the cellular environment and processes such as liquid-liquid phase separation may affect RNA folding and activity. The emerging RNA-ensemble-function paradigm is changing our perspective and understanding of RNA regulation, from in vitro to in vivo and from descriptive to predictive.
Topics: Animals; Gene Expression Regulation; Humans; RNA Folding; RNA Processing, Post-Transcriptional; RNA, Catalytic; RNA-Binding Proteins
PubMed: 31182864
DOI: 10.1038/s41580-019-0136-0