Wiley Interdisciplinary Reviews: RNA最新文献

Aminoacyl-tRNA synthetases form the protein family that controls the interpretation of the genetic code, with tRNA aminoacylation being the key chemical step during which an amino acid is assigned to a corresponding sequence of nucleic acids. In consequence, aminoacyl-tRNA synthetases have been studied in their physiological context, in disease states, and as tools for synthetic biology to enable the expansion of the genetic code. Here, we review the fundamentals of aminoacyl-tRNA synthetase biology and classification, with a focus on mammalian cytoplasmic enzymes. We compile evidence that the localization of aminoacyl-tRNA synthetases can be critical in health and disease. In addition, we discuss evidence from synthetic biology which made use of the importance of subcellular localization for efficient manipulation of the protein synthesis machinery. This article is categorized under: RNA Processing Translation > Translation Regulation RNA Processing > tRNA Processing RNA Export and Localization > RNA Localization.

Nucleic acid binding proteins regulate transcription, splicing, RNA stability, RNA localization, and translation, together tailoring gene expression in response to stimuli. Upon discovery, these proteins are typically classified as either DNA or RNA binding as defined by their in vivo functions; however, recent evidence suggests dual DNA and RNA binding by many of these proteins. High mobility group box (HMGB) proteins have a DNA binding HMGB domain, act as transcription factors and chromatin remodeling proteins, and are increasingly understood to interact with RNA as means to regulate gene expression. Herein, multiple layers of evidence that the HMGB family are dual DNA and RNA binding proteins is comprehensively reviewed. For example, HMGB proteins directly interact with RNA in vitro and in vivo, are localized to RNP granules involved in RNA processing, and their protein interactors are enriched in RNA binding proteins involved in RNA metabolism. Importantly, in cell-based systems, HMGB-RNA interactions facilitate protein-protein interactions, impact splicing outcomes, and modify HMGB protein genomic or cellular localization. Misregulation of these HMGB-RNA interactions are also likely involved in human disease. This review brings to light that as a family, HMGB proteins are likely to bind RNA which is essential to HMGB protein biology. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

Translation accuracy is one of the most critical factors for protein synthesis. It is regulated by the ribosome and its dynamic behavior, along with translation factors that direct ribosome rearrangements to make translation a uniform process. Earlier structural studies of the ribosome complex with arrested translation factors laid the foundation for an understanding of ribosome dynamics and the translation process as such. Recent technological advances in time-resolved and ensemble cryo-EM have made it possible to study translation in real time at high resolution. These methods provided a detailed view of translation in bacteria for all three phases: initiation, elongation, and termination. In this review, we focus on translation factors (in some cases GTP activation) and their ability to monitor and respond to ribosome organization to enable efficient and accurate translation. This article is categorized under: Translation > Ribosome Structure/Function Translation > Mechanisms.

Inosine triphosphate pyrophosphatase (ITPase), encoded by the ITPA gene in humans, is an important enzyme that preserves the integrity of cellular nucleotide pools by hydrolyzing the noncanonical purine nucleotides (deoxy)inosine and (deoxy)xanthosine triphosphate into monophosphates and pyrophosphate. Variants in the ITPA gene can cause partial or complete ITPase deficiency. Partial ITPase deficiency is benign but clinically relevant as it is linked to altered drug responses. Complete ITPase deficiency causes a severe multisystem disorder characterized by seizures and encephalopathy that is frequently associated with fatal infantile dilated cardiomyopathy. In the absence of ITPase activity, its substrate noncanonical nucleotides have the potential to accumulate and become aberrantly incorporated into DNA and RNA. Hence, the pathophysiology of ITPase deficiency could arise from metabolic imbalance, altered DNA or RNA regulation, or from a combination of these factors. Here, we review the known functions of ITPase and highlight recent work aimed at determining the molecular basis for ITPA-associated pathogenesis which provides evidence for RNA dysfunction. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.

Cellular machineries that drive and regulate gene expression often rely on the coordinated assembly and interaction of a multitude of proteins and RNA together called ribonucleoprotein complexes (RNPs). As such, it is challenging to fully reconstitute these cellular machines recombinantly and gain mechanistic understanding of how they operate and are regulated within the complex environment that is the cell. One strategy for overcoming this challenge is to perform single molecule fluorescence microscopy studies within crude or recombinantly supplemented cell extracts. This strategy enables elucidation of the interaction and kinetic behavior of specific fluorescently labeled biomolecules within RNPs under conditions that approximate native cellular environments. In this review, we describe single molecule fluorescence microcopy approaches that dissect RNP-driven processes within cellular extracts, highlighting general strategies used in these methods. We further survey biological advances in the areas of pre-mRNA splicing and transcription regulation that have been facilitated through this approach. Finally, we conclude with a summary of practical considerations for the implementation of the featured approaches to facilitate their broader future implementation in dissecting the mechanisms of RNP-driven cellular processes. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems.

The RNA polymerase III (Pol III) transcriptome is universally comprised of short, highly structured noncoding RNA (ncRNA). Through RNA-protein interactions, the Pol III transcriptome actuates functional activities ranging from nuclear gene regulation (7SK), splicing (U6, U6atac), and RNA maturation and stability (RMRP, RPPH1, Y RNA), to cytoplasmic protein targeting (7SL) and translation (tRNA, 5S rRNA). In higher eukaryotes, the Pol III transcriptome has expanded to include additional, recently evolved ncRNA species that effectively broaden the footprint of Pol III transcription to additional cellular activities. Newly evolved ncRNAs function as riboregulators of autophagy (vault), immune signaling cascades (nc886), and translation (Alu, BC200, snaR). Notably, upregulation of Pol III transcription is frequently observed in cancer, and multiple ncRNA species are linked to both cancer progression and poor survival outcomes among cancer patients. In this review, we outline the basic features and functions of the Pol III transcriptome, and the evidence for dysregulation and dysfunction for each ncRNA in cancer. When taken together, recurrent patterns emerge, ranging from shared functional motifs that include molecular scaffolding and protein sequestration, overlapping protein interactions, and immunostimulatory activities, to the biogenesis of analogous small RNA fragments and noncanonical miRNAs, augmenting the function of the Pol III transcriptome and further broadening its role in cancer. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Processing of Small RNAs RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

Numerous biological processes, such as transcription, replication, and translation, rely on protein-nucleic acid interactions (PNIs). Demonstrating the binding stability of protein-nucleic acid complexes is vital to deciphering the code for PNIs. Numerous web-based tools have been developed to attach importance to protein-nucleic acid stability, facilitating the prediction of PNIs characteristics rapidly. However, the data and tools are dispersed and lack comprehensive integration to understand the stability of PNIs better. In this review, we first summarize existing databases for evaluating the stability of protein-nucleic acid binding. Then, we compare and evaluate the pros and cons of web tools for forecasting the interaction energies of protein-nucleic acid complexes. Finally, we discuss the application of combining models and capabilities of PNIs. We may hope these web-based tools will facilitate the discovery of recognition mechanisms for protein-nucleic acid binding stability. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

Fusions of two genes can lead to the generation of chimeric RNAs, which may have a distinct functional role from their original molecules. Chimeric RNAs could encode novel functional proteins or serve as novel long noncoding RNAs (lncRNAs). The appearance of chimeric RNAs in a cell could help to generate new functionality and phenotypic diversity that might facilitate this cell to survive against new environmental stress. Several recent studies have demonstrated the functional roles of various chimeric RNAs in cancer progression and are considered as biomarkers for cancer diagnosis and sometimes even drug targets. Further, the growing evidence demonstrated the potential functional association of chimeric RNAs with cancer heterogeneity and drug resistance cancer evolution. Recent studies highlighted that chimeric RNAs also have functional potentiality in normal physiological processes. Several functionally potential chimeric RNAs were discovered in human cancer and normal cells in the last two decades. This could indicate that chimeric RNAs are the hidden layer of the human transcriptome that should be explored from the functional insights to better understand the functional evolution of the genome and disease development that could facilitate clinical practice improvements. This review summarizes the current knowledge of chimeric RNAs and highlights their functional, regulatory, and evolutionary impact on different cancers and normal physiological processes. Further, we will discuss the potential functional roles of a recently discovered novel class of chimeric RNAs named sense-antisense/cross-strand chimeric RNAs generated by the fusion of the bi-directional transcripts of the same gene. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs.

The 3'-end processing of mRNA is a co-transcriptional process that leads to the formation of a poly-adenosine tail on the mRNA and directly controls termination of the RNA polymerase II juggernaut. This process involves a megadalton complex composed of cleavage and polyadenylation specificity factors (CPSFs) that are able to recognize cis-sequence elements on nascent mRNA to then carry out cleavage and polyadenylation reactions. Recent structural and biochemical studies have defined the roles played by different subunits of the complex and provided a comprehensive mechanistic understanding of this machinery in yeast or metazoans. More recently, the discovery of small molecule inhibitors of CPSF function in Apicomplexa has stimulated interest in studying the specificities of this ancient eukaryotic machinery in these organisms. Although its function is conserved in Apicomplexa, the CPSF complex integrates a novel reader of the N6-methyladenosine (m6A). This feature, inherited from the plant kingdom, bridges m6A metabolism directly to 3'-end processing and by extension, to transcription termination. In this review, we will examine convergence and divergence of CPSF within the apicomplexan parasites and explore the potential of small molecule inhibition of this machinery within these organisms. This article is categorized under: RNA Processing > 3' End Processing RNA Processing > RNA Editing and Modification.

Ribonucleic acid (RNA) molecules are indispensable for cellular homeostasis in healthy and malignant cells. However, the functions of RNA extend well beyond that of a protein-coding template. Rather, both coding and non-coding RNA molecules function through critical interactions with a plethora of cellular molecules, including other RNAs, DNA, and proteins. Deconvoluting this RNA interactome, including the interacting partners, the nature of the interaction, and dynamic changes of these interactions in malignancies has yielded fundamental advances in knowledge and are emerging as a novel therapeutic strategy in cancer. Here, we present an RNA-centric review of recent advances in the field of RNA-RNA, RNA-protein, and RNA-DNA interactomic network analysis and their impact across the Hallmarks of Cancer. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.