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Journal Cover Wiley Interdisciplinary Reviews : RNA
  [SJR: 5.014]   [H-I: 21]   [3 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Online) 1757-7012
   Published by John Wiley and Sons Homepage  [1598 journals]
  • Dual roles of DNA repair enzymes in RNA biology/post‐transcriptional
           control
    • Authors: Jekaterina Vohhodina; D. Paul Harkin, Kienan I. Savage
      Abstract: Despite consistent research into the molecular principles of the DNA damage repair pathway for almost two decades, it has only recently been found that RNA metabolism is very tightly related to this pathway, and the two ancient biochemical mechanisms act in alliance to maintain cellular genomic integrity. The close links between these pathways are well exemplified by examining the base excision repair pathway, which is now well known for dual roles of many of its members in DNA repair and RNA surveillance, including APE1, SMUG1, and PARP1. With additional links between these pathways steadily emerging, this review aims to provide a summary of the emerging roles for DNA repair proteins in the post‐transcriptional regulation of RNAs. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-04-28T22:01:00.871135-05:
      DOI: 10.1002/wrna.1353
       
  • Structural insights into ribosome translocation
    • Authors: Clarence Ling; Dmitri N. Ermolenko
      Abstract: During protein synthesis, tRNA and mRNA are translocated from the A to P to E sites of the ribosome thus enabling the ribosome to translate one codon of mRNA after the other. Ribosome translocation along mRNA is induced by the universally conserved ribosome GTPase, elongation factor G (EF‐G) in bacteria and elongation factor 2 (EF‐2) in eukaryotes. Recent structural and single‐molecule studies revealed that tRNA and mRNA translocation within the ribosome is accompanied by cyclic forward and reverse rotations between the large and small ribosomal subunits parallel to the plane of the intersubunit interface. In addition, during ribosome translocation, the ‘head’ domain of small ribosomal subunit undergoes forward‐ and back‐swiveling motions relative to the rest of the small ribosomal subunit around the axis that is orthogonal to the axis of intersubunit rotation. tRNA/mRNA translocation is also coupled to the docking of domain IV of EF‐G into the A site of the small ribosomal subunit that converts the thermally driven motions of the ribosome and tRNA into the forward translocation of tRNA/mRNA inside the ribosome. Despite recent and enormous progress made in the understanding of the molecular mechanism of ribosome translocation, the sequence of structural rearrangements of the ribosome, EF‐G and tRNA during translocation is still not fully established and awaits further investigation. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-04-27T02:36:08.839733-05:
      DOI: 10.1002/wrna.1354
       
  • The evolving world of small RNAs from RNA viruses
    • Abstract: RNA virus infection in plants and invertebrates can produce virus‐derived small RNAs. These RNAs share features with host endogenous small interfering RNAs (siRNAs). They can potentially mediate RNA interference (RNAi) and related RNA silencing pathways, resulting in specific antiviral defense. Although most RNA silencing components such as Dicer, Ago2, and RISC are conserved among eukaryotic hosts, whether RNA virus infection in mammals can generate functional small RNAs that act in antiviral defense remains under discussion. Here, we review recent studies on the molecular and biochemical features of viral siRNAs and other virus‐derived small RNAs from infected plants, arthropods, nematodes, and vertebrates and discuss the genetic pathways for their biogenesis and their roles in antiviral activity. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-04-05T00:45:57.555264-05:
      DOI: 10.1002/wrna.1351
       
  • Dysregulated axonal RNA translation in amyotrophic lateral sclerosis
    • Authors: Kyota Yasuda; Stavroula Mili
      Abstract: Amyotrophic lateral sclerosis (ALS) is an adult‐onset motor neuron disease that has been associated with a diverse array of genetic changes. Prominent among these are mutations in RNA‐binding proteins (RBPs) or repeat expansions that give rise to toxic RNA species. RBPs are additionally central components of pathologic aggregates that constitute a disease hallmark, suggesting that dysregulation of RNA metabolism underlies disease progression. In the context of neuronal physiology, transport of RNAs and localized RNA translation in axons are fundamental to neuronal survival and function. Several lines of evidence suggest that axonal RNA translation is a central process perturbed by various pathogenic events associated with ALS. Dysregulated translation of specific RNA groups could underlie feedback effects that connect and reinforce disease manifestations. Among such candidates are RNAs encoding proteins involved in the regulation of microtubule dynamics. Further understanding of axonally dysregulated RNA targets and of the feedback mechanisms they induce could provide useful therapeutic insights. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-03-31T23:56:11.705342-05:
      DOI: 10.1002/wrna.1352
       
  • Regulatory effects of cotranscriptional RNA structure formation and
           transitions
    • Abstract: 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. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-03-29T20:40:44.644988-05:
      DOI: 10.1002/wrna.1350
       
  • Issue information
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  • Extracellular RNA in aging
    • Abstract: Since the discovery of extracellular RNA (exRNA) in circulation and other bodily fluids, there has been considerable effort to catalog and assess whether exRNAs can be used as markers for health and disease. A variety of exRNA species have been identified including messenger RNA and noncoding RNA such as microRNA (miRNA), small nucleolar RNA, transfer RNA, and long noncoding RNA. Age‐related changes in exRNA abundance have been observed, and it is likely that some of these transcripts play a role in aging. In this review, we summarize the current state of exRNA profiling in various body fluids and discuss age‐related changes in exRNA abundance that have been identified in humans and other model organisms. miRNAs, in particular, are a major focus of current research and we will highlight and discuss the potential role that specific miRNAs might play in age‐related phenotypes and disease. We will also review challenges facing this emerging field and various strategies that can be used for the validation and future use of exRNAs as markers of aging and age‐related disease. For further resources related to this article, please visit the WIREs website.
       
  • Fluorophore‐binding RNA aptamers and their applications
    • Abstract: Why image RNA' Of all the biological molecules, RNA exhibits the most diverse range of functions. Evidence suggests that transcription produces a wide range of noncoding RNAs (ncRNAs), both short (e.g., siRNAs, miRNAs) and long (e.g., telomeric RNAs) that regulate many aspects of gene expression, including the epigenetic processes that underlie cell fate determination, polarization, and morphogenesis. All these functions are realized through the exquisite temporal and spatial control of RNA expression levels and the stability of specific RNAs within well‐defined sub‐cellular compartments. Given the central importance of RNA in dictating cell behavior via gene‐related functions, there is a great demand for RNA imaging methods so as to determine the composition of the cellular ‘transcriptome’ and to acquire a complete spatial‐temporal profile of RNA localization. Recent advances in fluorophore‐binding RNA aptamers promise to provide exactly this knowledge, which can ultimately advance our understanding of cell function and behavior in conditions of health and disease, and in response to external stimuli. For further resources related to this article, please visit the WIREs website.
       
  • Advances in the characterization of RNA‐binding proteins
    • Abstract: From transcription, to transport, storage, and translation, RNA depends on association with different RNA‐binding proteins (RBPs). Methods based on next‐generation sequencing and protein mass‐spectrometry have started to unveil genome‐wide interactions of RBPs but many aspects still remain out of sight. How many of the binding sites identified in high‐throughput screenings are functional' A number of computational methods have been developed to analyze experimental data and to obtain insights into the specificity of protein–RNA interactions. How can theoretical models be exploited to identify RBPs' In addition to oligomeric complexes, protein and RNA molecules can associate into granular assemblies whose physical properties are still poorly understood. What protein features promote granule formation and what effects do these assemblies have on cell function' Here, we describe the newest in silico, in vitro, and in vivo advances in the field of protein–RNA interactions. We also present the challenges that experimental and computational approaches will have to face in future studies. For further resources related to this article, please visit the WIREs website. Protein and RNA molecules interact in vivo to accomplish a number of essential functions (e.g., transcription, translation, etc.). Deciphering these interactions is crucial to understand the mechanisms related to cell function and dysfunction. All these fundamental questions have started to be addressed thanks to the recent development of new experimental and computational techniques.
       
  • Roles of long noncoding RNAs in chromosome domains
    • Abstract: The cell nucleus is highly organized and functionally compartmentalized. Double‐stranded naked DNA is complexed with core histones and assembled into nucleosomes and chromatin, which are surrounded by nuclear domains composed of RNAs and proteins. Recently, three‐dimensional views of chromosome organization beyond the level of the nucleosome have been established and are composed of several layers of chromosome domains. Only a small portion of the human genome encodes proteins; the majority is pervasively transcribed into noncoding RNAs whose functions are under intensive investigation. Importantly, the questions of how nuclear retained noncoding RNAs play roles in orchestrating the chromatin structure that have been addressed. We discuss the novel noncoding RNA clusters, Eleanors, which are derived from a large chromatin domain. They accumulate at the site of their own transcription to form RNA clouds in the nucleus, and they activate gene expression in the chromatin domain. Noncoding RNAs have emerging roles in genome regulation that are integrated into the spatial organization of chromatin and the nucleus. For further resources related to this article, please visit the WIREs website. A chromatin domain containing ESR1 and coregulated genes is defined and activated by Eleanor ncRNAs in breast cancer cells.
       
  • Identifying fusion transcripts using next generation sequencing
    • Abstract: Fusion transcripts (i.e., chimeric RNAs) resulting from gene fusions have been used successfully for cancer diagnosis, prognosis, and therapeutic applications. In addition, many fusion transcripts are found in normal human cell lines and tissues, with some data supporting their role in normal physiology. Besides chromosomal rearrangement, intergenic splicing can generate them. Global identification of fusion transcripts becomes possible with the help of next generation sequencing technology like RNA‐Seq. In the past decade, major advancements have been made for chimeric RNA discovery due to the development of advanced sequencing platform and software packages. However, current software tools behave differently in terms of specificity, sensitivity, time, and computational memory usage. Recent benchmarking studies showed that none of the tools are inclusive. The development of high performance (accurate and fast), and user‐friendly fusion detection tool/pipeline is still an open quest. In this article, we review the existing software packages for fusion detection. We explain the methods of the tools, and discuss various factors that affect fusion detection. We summarize conclusions drawn from several comparative studies, and then discuss some of the pitfalls of these studies. We also describe the limitations of current tools, and suggest directions for future development. For further resources related to this article, please visit the WIREs website.
       
  • The nuts and bolts of the endogenous spliceosome
    • Abstract: The complex life of pre‐mRNA from transcription to the production of mRNA that can be exported from the nucleus to the cytoplasm to encode for proteins entails intricate coordination and regulation of a network of processing events. Coordination is required between transcription and splicing and between several processing events including 5′ and 3′ end processing, splicing, alternative splicing and editing that are major contributors to the diversity of the human proteome, and occur within a huge and dynamic macromolecular machine—the endogenous spliceosome. Detailed mechanistic insight of the splicing reaction was gained from studies of the in vitro spliceosome assembled on a single intron. Because most pre‐mRNAs are multiintronic that undergo alternative splicing, the in vivo splicing machine requires additional elements to those of the in vitro machine, to account for all these diverse functions. Information about the endogenous spliceosome is emerging from imaging studies in intact and live cells that support the cotranscriptional commitment to splicing model and provide information about splicing kinetics in vivo. Another source comes from studies of the in vivo assembled spliceosome, isolated from cell nuclei under native conditions—the supraspliceosome—that individually package pre‐mRNA transcripts of different sizes and number of introns into complexes of a unique structure, indicating their universal nature. Recent years have portrayed new players affecting alternative splicing and novel connections between splicing, transcription and chromatin. The challenge ahead is to elucidate the structure and function of the endogenous spliceosome and decipher the regulation and coordination of its network of processing activities. For further resources related to this article, please visit the WIREs website. Network of functions and interactions within the endogenous spliceosome, including: 5′ end capping (5′ cap), 3′ end processing and polyadenylation (Poly A), RNA editing, splicing, alternative splicing, and processing of intronic small noncoding RNA (IVS sncRNA).
       
  • Evolutionary clues in lncRNAs
    • Abstract: The diversity of long non‐coding RNAs (lncRNAs) in the human transcriptome is in stark contrast to the sparse exploration of their functions concomitant with their conservation and evolution. The pervasive transcription of the largely non‐coding human genome makes the evolutionary age and conservation patterns of lncRNAs to a topic of interest. Yet it is a fairly unexplored field and not that easy to determine as for protein‐coding genes. Although there are a few experimentally studied cases, which are conserved at the sequence level, most lncRNAs exhibit weak or untraceable primary sequence conservation. Recent studies shed light on the interspecies conservation of secondary structures among lncRNA homologs by using diverse computational methods. This highlights the importance of structure on functionality of lncRNAs as opposed to the poor impact of primary sequence changes. Further clues in the evolution of lncRNAs are given by selective constraints on non‐coding gene structures (e.g., promoters or splice sites) as well as the conservation of prevalent spatio‐temporal expression patterns. However, a rapid evolutionary turnover is observable throughout the heterogeneous group of lncRNAs. This still gives rise to questions about its functional meaning. For further resources related to this article, please visit the WIREs website.
       
  • mRNA methylation by NSUN2 in cell proliferation
    • Abstract: Methylation is a prevalent post‐transcriptional modification that occurs in almost all RNA species. NSUN2, a nucleolar RNA methyltransferase, has been shown to methylate mRNAs encoding factors that control cell division and growth arrest, thereby affecting their stability and/or translation. Here, the author summarizes the recent progress in understanding NSUN2‐mediated mRNA methylation and its implications in cell proliferation and senescence. For further resources related to this article, please visit the WIREs website.
       
  • Modulating splicing with small molecular inhibitors of the spliceosome
    • Abstract: Small molecule inhibitors that target components of the spliceosome have great potential as tools to probe splicing mechanism and dissect splicing regulatory networks in cells. These compounds also hold promise as drug leads for diseases in which splicing regulation plays a critical role, including many cancers. Because the spliceosome is a complicated and dynamic macromolecular machine comprised of many RNA and protein components, a variety of compounds that interfere with different aspects of spliceosome assembly is needed to probe its function. By screening chemical libraries with high‐throughput splicing assays, several labs have added to the collection of splicing inhibitors, although the mechanistic insight into splicing yielded from the initial compound hits is somewhat limited so far. In contrast, SF3B1 inhibitors stand out as a great example of what can be accomplished with small molecule tools. This group of compounds were first discovered as natural products that are cytotoxic to cancer cells, and then later shown to target the core spliceosome protein SF3B1. The inhibitors have since been used to uncover details of SF3B1 mechanism in the spliceosome and its impact on gene expression in cells. Continuing structure activity relationship analysis of the compounds is also making progress in identifying chemical features key to their function, which is critical in understanding the mechanism of SF3B1 inhibition. The knowledge is also important for the design of analogs with new and useful features for both splicing researchers and clinicians hoping to exploit splicing as pressure point to target in cancer therapy. For further resources related to this article, please visit the WIREs website. Small molecule inhibitors as tools to study the mechanics of the pre‐mRNA splicing by the spliceosome
       
  • New insights into decapping enzymes and selective mRNA decay
    • Abstract: Removal of the 5′ end cap is a critical determinant controlling mRNA stability and efficient gene expression. Removal of the cap is exquisitely controlled by multiple direct and indirect regulators that influence association with the cap and the catalytic step. A subset of these factors directly stimulate activity of the decapping enzyme, while others influence remodeling of factors bound to mRNA and indirectly stimulate decapping. Furthermore, the components of the general decapping machinery can also be recruited by mRNA‐specific regulatory proteins to activate decapping. The Nudix hydrolase, Dcp2, identified as a first decapping enzyme, cleaves capped mRNA and initiates 5′–3′ degradation. Extensive studies on Dcp2 led to broad understanding of its activity and the regulation of transcript specific decapping and decay. Interestingly, seven additional Nudix proteins possess intrinsic decapping activity in vitro and at least two, Nudt16 and Nudt3, are decapping enzymes that regulate mRNA stability in cells. Furthermore, a new class of decapping proteins within the DXO family preferentially function on incompletely capped mRNAs. Importantly, it is now evident that each of the characterized decapping enzymes predominantly modulates only a subset of mRNAs, suggesting the existence of multiple decapping enzymes functioning in distinct cellular pathways. For further resources related to this article, please visit the WIREs website.
       
  • Transcending the prediction paradigm: novel applications of SHAPE to RNA
           function and evolution
    • Abstract: Selective 2′‐hydroxyl acylation analyzed by primer extension (SHAPE) provides information on RNA structure at single‐nucleotide resolution. It is most often used in conjunction with RNA secondary structure prediction algorithms as a probabilistic or thermodynamic restraint. With the recent advent of ultra‐high‐throughput approaches for collecting SHAPE data, the applications of this technology are extending beyond structure prediction. In this review, we discuss recent applications of SHAPE data in the transcriptomic context and how this new experimental paradigm is changing our understanding of these experiments and RNA folding in general. SHAPE experiments probe both the secondary and tertiary structure of an RNA, suggesting that model‐free approaches for within and comparative RNA structure analysis can provide significant structural insight without the need for a full structural model. New methods incorporating SHAPE at different nucleotide resolutions are required to parse these transcriptomic data sets to transcend secondary structure modeling with global structural metrics. These ‘multiscale’ approaches provide deeper insights into RNA global structure, evolution, and function in the cell. For further resources related to this article, please visit the WIREs website.
       
  • Translating the epitranscriptome
    • Abstract: RNA modifications are indispensable for the translation machinery to provide accurate and efficient protein synthesis. Whereas the importance of transfer RNA (tRNA) and ribosomal RNA (rRNA) modifications has been well described and is unquestioned for decades, the significance of internal messenger RNA (mRNA) modifications has only recently been revealed. Novel experimental methods have enabled the identification of thousands of modified sites within the untranslated and translated regions of mRNAs. Thus far, N 6‐methyladenosine (m6A), pseudouridine (Ψ), 5‐methylcytosine (m5C) and N 1‐methyladenosine (m1A) were identified in eukaryal, and to some extent in prokaryal mRNAs. Several of the functions of these mRNA modifications have previously been reported, but many aspects remain elusive. Modifications can be important factors for the direct regulation of protein synthesis. The potential diversification of genomic information and regulation of RNA expression through editing and modifying mRNAs is versatile and many questions need to be addressed to completely elucidate the role of mRNA modifications. Herein, we summarize and highlight some recent findings on various co‐ and post‐transcriptional modifications, describing the impact of these processes on gene expression, with emphasis on protein synthesis. For further resources related to this article, please visit the WIREs website.
       
  • The organization and regulation of mRNA–protein complexes
    • Abstract: In a eukaryotic cell, each messenger RNA (mRNA) is bound to a variety of proteins to form an mRNA–protein complex (mRNP). Together, these proteins impact nearly every step in the life cycle of an mRNA and are critical for the proper control of gene expression. In the cytoplasm, for instance, mRNPs affect mRNA translatability and stability and provide regulation of specific transcripts as well as global, transcriptome‐wide control. mRNPs are complex, diverse, and dynamic, and so they have been a challenge to understand. But the advent of high‐throughput sequencing technology has heralded a new era in the study of mRNPs. Here, I will discuss general principles of cytoplasmic mRNP organization and regulation. Using microRNA‐mediated repression as a case study, I will focus on common themes in mRNPs and highlight the interplay between mRNP composition and posttranscriptional regulation. mRNPs are an important control point in regulating gene expression, and while the study of these fascinating complexes presents remaining challenges, recent advances provide a critical lens for deciphering gene regulation. For further resources related to this article, please visit the WIREs website.
       
  • The role of mRNA structure in bacterial translational regulation
    • Abstract: The characteristics of bacterial messenger RNAs (mRNAs) that influence translation efficiency provide many convenient handles for regulation of gene expression, especially when coupled with the processes of transcription termination and mRNA degradation. An mRNA's structure, especially near the site of initiation, has profound consequences for how readily it is translated. This property allows bacterial gene expression to be altered by changes to mRNA structure induced by temperature, or interactions with a wide variety of cellular components including small molecules, other RNAs (such as sRNAs and tRNAs), and RNA‐binding proteins. This review discusses the links between mRNA structure and translation efficiency, and how mRNA structure is manipulated by conditions and signals within the cell to regulate gene expression. The range of RNA regulators discussed follows a continuum from very complex tertiary structures such as riboswitch aptamers and ribosomal protein‐binding sites to thermosensors and mRNA:sRNA interactions that involve only base‐pairing interactions. Furthermore, the high degrees of diversity observed for both mRNA structures and the mechanisms by which inhibition of translation occur have significant consequences for understanding the evolution of bacterial translational regulation. For further resources related to this article, please visit the WIREs website.
       
  • Posttranslational control of HuR function
    • Abstract: The RNA‐binding protein HuR (human antigen R) associates with numerous transcripts, coding and noncoding, and controls their splicing, localization, stability, and translation. Through its regulation of target transcripts, HuR has been implicated in cellular events including proliferation, senescence, differentiation, apoptosis, and the stress and immune responses. In turn, HuR influences processes such as cancer and inflammation. HuR function is primarily regulated through posttranslational modifications that alter its subcellular localization and its ability to bind target RNAs; such modifications include phosphorylation, methylation, ubiquitination, NEDDylation, and proteolytic cleavage. In this review, we describe the modifications that impact upon HuR function on gene expression programs and disease states. For further resources related to this article, please visit the WIREs website.
       
  • Small molecules targeting viral RNA
    • Abstract: Highly conserved noncoding RNA (ncRNA) elements in viral genomes and transcripts offer new opportunities to expand the repertoire of drug targets for the development of antiinfective therapy. Ligands binding to ncRNA architectures are able to affect interactions, structural stability or conformational changes and thereby block processes essential for viral replication. Proof of concept for targeting functional RNA by small molecule inhibitors has been demonstrated for multiple viruses with RNA genomes. Strategies to identify antiviral compounds as inhibitors of ncRNA are increasingly emphasizing consideration of drug‐like properties of candidate molecules emerging from screening and ligand design. Recent efforts of antiviral lead discovery for RNA targets have provided drug‐like small molecules that inhibit viral replication and include inhibitors of human immunodeficiency virus (HIV), hepatitis C virus (HCV), severe respiratory syndrome coronavirus (SARS CoV), and influenza A virus. While target selectivity remains a challenge for the discovery of useful RNA‐binding compounds, a better understanding is emerging of properties that define RNA targets amenable for inhibition by small molecule ligands. Insight from successful approaches of targeting viral ncRNA in HIV, HCV, SARS CoV, and influenza A will provide a basis for the future exploration of RNA targets for therapeutic intervention in other viral pathogens which create urgent, unmet medical needs. Viruses for which targeting ncRNA components in the genome or transcripts may be promising include insect‐borne flaviviruses (Dengue, Zika, and West Nile) and filoviruses (Ebola and Marburg). For further resources related to this article, please visit the WIREs website.
       
  • Going global: the new era of mapping modifications in RNA
    • Abstract: The post‐transcriptional modification of RNA by the addition of one or more chemical groups has been known for over 50 years. These chemical modifications, once thought to be static, are now being discovered to play key regulatory roles in gene expression. The advent of massive parallel sequencing of RNA (RNA‐seq) now allows us to probe the complexity of cellular RNA and how chemically altering RNA structure expands the RNA vocabulary. Here we present an overview of the various strategies and technologies that are available to profile RNA chemical modifications at the cellular level. These strategies can be characterized as targeted and untargeted approaches: targeted strategies are developed for one single chemical modification while untargeted strategies are more broadly applicable to a range of such chemical changes. Key for all of these approaches is the ability to locate modifications within the RNA sequence. While most of these methods are built upon an RNA‐Seq pipeline, alternative approaches based on mass spectrometry or conventional DNA sequencing retain value in the overall analysis process. We also look forward toward future opportunities and technologies that may expand the types of modifications that can be globally profiled. Given the ever increasing recognition that these RNA chemical modifications play important biological roles, a variety of methods, preferably orthogonal approaches, will be required to globally identify, validate and quantify RNA chemical modifications found in the transcriptome. For further resources related to this article, please visit the WIREs website.
       
  • Hallmarks of cancer and AU‐rich elements
    • Abstract: Post‐transcriptional control of gene expression is aberrant in cancer cells. Sustained stabilization and enhanced translation of specific mRNAs are features of tumor cells. AU‐rich elements (AREs), cis‐acting mRNA decay determinants, play a major role in the posttranscriptional regulation of many genes involved in cancer processes. This review discusses the role of aberrant ARE‐mediated posttranscriptional processes in each of the hallmarks of cancer, including sustained cellular growth, resistance to apoptosis, angiogenesis, invasion, and metastasis. For further resources related to this article, please visit the WIREs website.
       
  • Translational regulation in blood stages of the malaria parasite
           Plasmodium spp.: systems‐wide studies pave the way
    • Abstract: The malaria parasite Plasmodium spp. varies the expression profile of its genes depending on the host it resides in and its developmental stage. Virtually all messenger RNA (mRNA) is expressed in a monocistronic manner, with transcriptional activation regulated at the epigenetic level and by specialized transcription factors. Furthermore, recent systems‐wide studies have identified distinct mechanisms of post‐transcriptional and translational control at various points of the parasite lifecycle. Taken together, it is evident that ‘just‐in‐time’ transcription and translation strategies coexist and coordinate protein expression during Plasmodium development, some of which we review here. In particular, we discuss global and specific mechanisms that control protein translation in blood stages of the human malaria parasite Plasmodium falciparum, once a cytoplasmic mRNA has been generated, and its crosstalk with mRNA decay and storage. We also focus on the widespread translational delay observed during the 48‐hour blood stage lifecycle of P. falciparum—for over 30% of transcribed genes, including virulence factors required to invade erythrocytes—and its regulation by cis‐elements in the mRNA, RNA‐processing enzymes and RNA‐binding proteins; the first‐characterized amongst these are the DNA‐ and RNA‐binding Alba proteins. More generally, we conclude that translational regulation is an emerging research field in malaria parasites and propose that its elucidation will not only shed light on the complex developmental program of this parasite, but may also reveal mechanisms contributing to drug resistance and define new targets for malaria intervention strategies. For further resources related to this article, please visit the WIREs website.
       
  • Lights, camera, action! Capturing the spliceosome and pre‐mRNA
           splicing with single‐molecule fluorescence microscopy
    • Abstract: The process of removing intronic sequences from a precursor to messenger RNA (pre‐mRNA) to yield a mature mRNA transcript via splicing is an integral step in eukaryotic gene expression. Splicing is carried out by a cellular nanomachine called the spliceosome that is composed of RNA components and dozens of proteins. Despite decades of study, many fundamentals of spliceosome function have remained elusive. Recent developments in single‐molecule fluorescence microscopy have afforded new tools to better probe the spliceosome and the complex, dynamic process of splicing by direct observation of single molecules. These cutting‐edge technologies enable investigators to monitor the dynamics of specific splicing components, whole spliceosomes, and even cotranscriptional splicing within living cells. For further resources related to this article, please visit the WIREs website.
       
  • RNA‐Seq methods for transcriptome analysis
    • Abstract: Deep sequencing has been revolutionizing biology and medicine in recent years, providing single base‐level precision for our understanding of nucleic acid sequences in high throughput fashion. Sequencing of RNA, or RNA‐Seq, is now a common method to analyze gene expression and to uncover novel RNA species. Aspects of RNA biogenesis and metabolism can be interrogated with specialized methods for cDNA library preparation. In this study, we review current RNA‐Seq methods for general analysis of gene expression and several specific applications, including isoform and gene fusion detection, digital gene expression profiling, targeted sequencing and single‐cell analysis. In addition, we discuss approaches to examine aspects of RNA in the cell, technical challenges of existing RNA‐Seq methods, and future directions. For further resources related to this article, please visit the WIREs website.
       
  • Ribosome‐based quality control of mRNA and nascent peptides
    • Abstract: Quality control processes are widespread and play essential roles in detecting defective molecules and removing them in order to maintain organismal fitness. Aberrant messenger RNA (mRNA) molecules, unless properly managed, pose a significant hurdle to cellular proteostasis. Often mRNAs harbor premature stop codons, possess structures that present a block to the translational machinery, or lack stop codons entirely. In eukaryotes, the three cytoplasmic mRNA‐surveillance processes, nonsense‐mediated decay (NMD), no‐go decay (NGD), and nonstop decay (NSD), evolved to cope with these aberrant mRNAs, respectively. Nonstop mRNAs and mRNAs that inhibit translation elongation are especially problematic as they sequester valuable ribosomes from the translating ribosome pool. As a result, in addition to RNA degradation, NSD and NGD are intimately coupled to ribosome rescue in all domains of life. Furthermore, protein products produced from all three classes of defective mRNAs are more likely to malfunction. It is not surprising then that these truncated nascent protein products are subject to degradation. Over the past few years, many studies have begun to document a central role for the ribosome in initiating the RNA and protein quality control processes. The ribosome appears to be responsible for recognizing the target mRNAs as well as for recruiting the factors required to carry out the processes of ribosome rescue and nascent protein decay. For further resources related to this article, please visit the WIREs website.
       
  • Expected and unexpected features of protein‐binding RNA aptamers
    • Abstract: RNA molecules with high affinity to specific proteins can be isolated from libraries of up to 1016 different RNA sequences by systematic evolution of ligands by exponential enrichment (SELEX). These so‐called protein‐binding RNA aptamers are often interesting, e.g., as modulators of protein function for therapeutic use, for probing the conformations of proteins, for studies of basic aspects of nucleic acid–protein interactions, etc. Studies on the interactions between RNA aptamers and proteins display a number of expected and unexpected features, including the chemical nature of the interacting RNA‐protein surfaces, the conformation of protein‐bound aptamer versus free aptamer, the conformation of aptamer‐bound protein versus free protein, and the effects of aptamers on protein function. Here, we review current insights into the details of RNA aptamer–protein interactions. For further resources related to this article, please visit the WIREs website.
       
  • Anatomy of RISC: how do small RNAs and chaperones activate Argonaute
           proteins'
    • Abstract: RNA silencing is a eukaryote‐specific phenomenon in which microRNAs and small interfering RNAs degrade messenger RNAs containing a complementary sequence. To this end, these small RNAs need to be loaded onto an Argonaute protein (AGO protein) to form the effector complex referred to as RNA‐induced silencing complex (RISC). RISC assembly undergoes multiple and sequential steps with the aid of Hsc70/Hsp90 chaperone machinery. The molecular mechanisms for this assembly process remain unclear, despite their significance for the development of gene silencing techniques and RNA interference‐based therapeutics. This review dissects the currently available structures of AGO proteins and proposes models and hypotheses for RISC assembly, covering the conformation of unloaded AGO proteins, the chaperone‐assisted duplex loading, and the slicer‐dependent and slicer‐independent duplex separation. The differences in the properties of RISC between prokaryotes and eukaryotes will also be clarified. For further resources related to this article, please visit the WIREs website.
       
  • Exosome‐mediated small RNA delivery for gene therapy
    • Abstract: Small RNAs, including small interfering RNAs (siRNA) and microRNAs (miRNA), are emerging as promising therapeutic drugs against a wide array of diseases. The key obstacle for the successful clinical application of small RNAs is to develop a safe delivery system directed at the target tissues only. Current small RNA transfer techniques use viruses or synthetic agents as delivery vehicles. The replacement of these delivery vehicles with a low toxicity and high target‐specific approach is essential for making small RNA therapy feasible. Because exosomes have the intrinsic ability to traverse biological barriers and to naturally transport functional small RNAs between cells, they represent a novel and exciting delivery vehicle for the field of small RNA therapy. As therapeutic delivery agents, exosomes will potentially be better tolerated by the immune system because they are natural nanocarriers derived from endogenous cells. Furthermore, exosomes derived from genetically engineered cells can deliver small RNAs to target tissues and cells. Thus, exosome‐based delivery of small RNAs may provide an untapped, effective delivery strategy to overcome impediments such as inefficiency, nonspecificity, and immunogenic reactions. In this review, we briefly describe how exosomal small RNAs function in recipient cells. Furthermore, we provide an update and overview of new findings that reveal the potential applications of exosome‐based small RNA delivery as therapeutics in clinical settings. For further resources related to this article, please visit the WIREs website.
       
  • Nonsense‐mediated mRNA decay: novel mechanistic insights and
           biological impact
    • Abstract: Nonsense‐mediated mRNA decay (NMD) was originally coined to define a quality control mechanism that targets mRNAs with truncated open reading frames due to the presence of a premature termination codon. Meanwhile, it became clear that NMD has a much broader impact on gene expression and additional biological functions beyond quality control are continuously being discovered. We review here the current views regarding the molecular mechanisms of NMD, according to which NMD ensues on mRNAs that fail to terminate translation properly, and point out the gaps in our understanding. We further summarize the recent literature on an ever‐rising spectrum of biological processes in which NMD appears to be involved, including homeostatic control of gene expression, development and differentiation, as well as viral defense. For further resources related to this article, please visit the WIREs website.
       
  • Function and evolution of the long noncoding RNA circuitry orchestrating
           X‐chromosome inactivation in mammals
    • Abstract: X‐chromosome inactivation (XCI) is a chromosome‐wide regulatory process that ensures dosage compensation for X‐linked genes in Theria. XCI is established during early embryogenesis and is developmentally regulated. Different XCI strategies exist in mammalian infraclasses and the regulation of this process varies also among closely related species. In Eutheria, initiation of XCI is orchestrated by a cis‐acting locus, the X‐inactivation center (Xic), which is particularly enriched in genes producing long noncoding RNAs (lncRNAs). Among these, Xist generates a master transcript that coats and propagates along the future inactive X‐chromosome in cis, establishing X‐chromosome wide transcriptional repression through interaction with several protein partners. Other lncRNAs also participate to the regulation of X‐inactivation but the extent to which their function has been maintained in evolution is still poorly understood. In Metatheria, Xist is not conserved, but another, evolutionary independent lncRNA with similar properties, Rsx, has been identified, suggesting that lncRNA‐mediated XCI represents an evolutionary advantage. Here, we review current knowledge on the interplay of X chromosome‐encoded lncRNAs in ensuring proper establishment and maintenance of chromosome‐wide silencing, and discuss the evolutionary implications of the emergence of species‐specific lncRNAs in the control of XCI within Theria. For further resources related to this article, please visit the WIREs website.
       
  • Virus‐derived small RNAs: molecular footprints of
           host–pathogen interactions
    • Abstract: Viruses are obligatory intracellular parasites that require the host machinery to replicate. During their replication cycle, viral RNA intermediates can be recognized and degraded by different antiviral mechanisms that include RNA decay, RNA interference, and RNase L pathways. As a consequence of viral RNA degradation, infected cells can accumulate virus‐derived small RNAs at high levels compared to cellular molecules. These small RNAs are imprinted with molecular characteristics that reflect their origin. First, small RNAs can be used to reconstruct viral sequences and identify the virus from which they originated. Second, other molecular features of small RNAs such as size, polarity, and base preferences depend on the type of viral substrate and host mechanism of degradation. Thus, the pattern of small RNAs generated in infected cells can be used as a molecular footprint to identify and characterize viruses independent on sequence homology searches against known references. Hence, sequencing of small RNAs obtained from infected cells enables virus discovery and characterization using both sequence‐dependent strategies and novel pattern‐based approaches. Recent studies are helping unlock the full application of small RNA sequencing for virus discovery and characterization. For further resources related to this article, please visit the WIREs website.
       
 
 
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