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Journal Cover Wiley Interdisciplinary Reviews : RNA
  [SJR: 4.563]   [H-I: 36]   [3 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Online) 1757-7012
   Published by John Wiley and Sons Homepage  [1611 journals]
  • Cover Image, Volume 7, Issue 6
    • Authors: Shailesh Kumar; Sundus Khalid Razzaq, Angie Duy Vo, Mamta Gautam, Hui Li
      Abstract: The cover image, by Shailesh Kumar et al., is based on the Advanced Review Identifying fusion transcripts using next generation sequencing,
      DOI : 10.1002/wrna.1382.The cover image, by Shailesh Kumar et al., is based on the Advanced Review Identifying fusion transcripts using next generation sequencing,
      DOI : 10.1002/wrna.1382.
      PubDate: 2016-10-14T21:06:54.363929-05:
  • Posttranscriptional regulation of intestinal epithelial integrity by
           noncoding RNAs
    • Authors: Jun-Yao Wang; Lan Xiao, Jian-Ying Wang
      Abstract: Maintenance of the gut epithelial integrity under stressful environments requires epithelial cells to rapidly elicit changes in gene expression patterns to regulate their survival, adapt to stress, and keep epithelial homeostasis. Disruption of the intestinal epithelial integrity occurs commonly in patients with various critical illnesses, leading to the translocation of luminal toxic substances and bacteria to the blood stream. Recently, noncoding RNAs (ncRNAs) have emerged as a novel class of master regulators of gene expression and are fundamentally involved in many aspects of gut mucosal regeneration, protection, and epithelial barrier function. Here, we highlight the roles of several intestinal epithelial tissue-specific microRNAs, including miR-222, miR-29b, miR-503, and miR-195, and long ncRNAs such as H19 and SPRY4-IT1 in the regulation of cell proliferation, apoptosis, migration, and cell-to-cell interactions and also further analyze the mechanisms through which ncRNAs and their interactions with RNA-binding proteins modulate the stability and translation of target mRNAs.For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-10-04T21:56:05.306232-05:
      DOI: 10.1002/wrna.1399
  • Advances in RNA molecular dynamics: a simulator's guide to RNA force
    • Authors: Sweta Vangaveti; Srivathsan V. Ranganathan, Alan A. Chen
      Abstract: Molecular simulations have become an essential tool for biochemical research. When they work properly, they are able to provide invaluable interpretations of experimental results and ultimately provide novel, experimentally testable predictions. Unfortunately, not all simulation models are created equal, and with inaccurate models it becomes unclear what is a bona fide prediction versus a simulation artifact. RNA models are still in their infancy compared to the many robust protein models that are widely in use, and for that reason the number of RNA force field revisions in recent years has been rapidly increasing. As there is no universally accepted ‘best’ RNA force field at the current time, RNA simulators must decide which one is most suited to their purposes, cognizant of its essential assumptions and their inherent strengths and weaknesses. Hopefully, armed with a better understanding of what goes inside the simulation ‘black box,’ RNA biochemists can devise novel experiments and provide crucial thermodynamic and structural data that will guide the development and testing of improved RNA models.For further resources related to this article, please visit the WIREs website.Accurate simulation models for RNA require a delicate balancing of underlying driving forces.
      PubDate: 2016-10-04T21:05:39.567202-05:
      DOI: 10.1002/wrna.1396
  • Ligand-dependent ribozymes
    • Authors: Michele Felletti; Jörg S. Hartig
      Abstract: The discovery of catalytic RNA (ribozymes) more than 30 years ago significantly widened the horizon of RNA-based functions in natural systems. Similarly to the activity of protein enzymes that are often modulated by the presence of an interaction partner, some examples of naturally occurring ribozymes are influenced by ligands that can either act as cofactors or allosteric modulators. Recent discoveries of new and widespread ribozyme motifs in many different genetic contexts point toward the existence of further ligand-dependent RNA catalysts. In addition to the presence of ligand-dependent ribozymes in nature, researchers have engineered ligand dependency into natural and artificial ribozymes. Because RNA functions can often be assembled in a truly modular way, many different systems have been obtained utilizing different ligand-sensing domains and ribozyme activities in diverse applications. We summarize the occurrence of ligand-dependent ribozymes in nature and the many examples realized by researchers that engineered ligand-dependent catalytic RNA motifs. We will also highlight methods for obtaining ligand dependency as well as discuss the many interesting applications of ligand-controlled catalytic RNAs.For further resources related to this article, please visit the WIREs website.Ligand-dependent ribozymes are found in nature. They can also be generated artificially for constructing biosensors and synthetic genetic switches.
      PubDate: 2016-09-30T01:35:49.546796-05:
      DOI: 10.1002/wrna.1395
  • RNA‐binding proteins implicated in neurodegenerative diseases
    • Authors: Mark R Cookson
      Abstract: Gene expression is regulated at many levels, including after generation of the primary RNA transcript from DNA but before translation into protein. Such post‐translational gene regulation occurs via the action of a multitude of RNA binding proteins and include varied actions from splicing to regulation of association with the translational machinery. Primary evidence that such processes might contribute to disease mechanisms in neurodegenerative disorders comes from the observation of mutations in RNA binding proteins, particularly in diseases in the amyotrophic lateral sclerosis‐frontotemporal dementia spectrum and in some forms of ataxia and tremor. The bulk of evidence from recent surveys of the types of RNA species that are affected in these disorders suggests a global deregulation of control rather than a very small number of RNA species, although why some groups of neurons are sensitive to these changes is not well understood. Overall, these data suggest that neurodegeneration can be initiated by mutations in RNA binding proteins and, as a corollary, that neurons are particularly sensitive to loss of control of gene expression at the post‐transcriptional level. Such observations have implications not only for understanding the nature of neurodegenerative disorders but also how we might intervene therapeutically in these diseases.For further resources related to this article, please visit the WIREs website.Mutated RNA binding proteins cause neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) by disrupting the information flow from DNA to protein.
      PubDate: 2016-09-23T00:30:26.664262-05:
      DOI: 10.1002/wrna.1397
  • Neurodegeneration and RNA‐binding proteins
    • Authors: Laura De Conti; Marco Baralle, Emanuele Buratti
      Abstract: In the eukaryotic nucleus, RNA‐binding proteins (RBPs) play a very important role in the life cycle of both coding and noncoding RNAs. As soon as they are transcribed, in fact, all RNA molecules within a cell are bound by distinct sets of RBPs that have the task of regulating its correct processing, transport, stability, and function/translation up to its final degradation. These tasks are particularly important in cells that have a complex RNA metabolism, such as neurons. Not surprisingly, therefore, recent findings have shown that the misregulation of genes involved in RNA metabolism or the autophagy/proteasome pathway plays an important role in the onset and progression of several neurodegenerative diseases. In this article, we aim to review the recent advances that link neurodegenerative processes and RBP proteins.For further resources related to this article, please visit the WIREs website.RNA‐binding proteins play an essential role in neuronal metabolism and when their expression is altered, this can lead to neurodegeneration and diseases.
      PubDate: 2016-09-22T23:35:29.149832-05:
      DOI: 10.1002/wrna.1394
  • AUF1 regulation of coding and noncoding RNA
    • Authors: Elizabeth J.F. White; Aerielle E. Matsangos, Gerald M. Wilson
      Abstract: AUF1 is a family of four RNA‐binding proteins (RBPs) generated by alternative pre‐messenger RNA (pre-mRNA) splicing, with canonical roles in controlling the stability and/or translation of mRNA targets based on recognition of AU‐rich sequences within mRNA 3′ untranslated regions. However, recent studies identifying AUF1 target sites across the transcriptome have revealed that these canonical functions are but a subset of its roles in posttranscriptional regulation of gene expression. In this review, we describe recent developments in our understanding of the RNA‐binding properties of AUF1 together with their biochemical implications and roles in directing mRNA decay and translation. This is then followed by a survey of newly discovered activities for AUF1 proteins in control of miRNA synthesis and function, including miRNA assembly into microRNA (miRNA)‐loaded RNA‐induced silencing complexes (miRISCs), miRISC targeting to mRNA substrates, interplay with an expanding network of other cellular RBPs, and reciprocal regulatory relationships between miRNA and AUF1 synthesis. Finally, we discuss recently reported relationships between AUF1 and long noncoding RNAs and regulatory roles on viral RNA substrates. Cumulatively, these findings have significantly expanded our appreciation of the scope and diversity of AUF1 functions in the cell, and are prompting an exciting array of new questions moving forward.For further resources related to this article, please visit the WIREs website.AUF1 enhances loading of select miRNAs into RISCs and can also regulate miRISC access to mRNA substrates.
      PubDate: 2016-09-13T01:55:42.866741-05:
      DOI: 10.1002/wrna.1393
  • Emerging roles and context of circular RNAs
    • Authors: Amaresh C. Panda; Ioannis Grammatikakis, Rachel Munk, Myriam Gorospe, Kotb Abdelmohsen
      Abstract: Circular RNAs (circRNAs) represent a large class of noncoding RNAs (ncRNAs) that have recently emerged as regulators of gene expression. They have been shown to suppress microRNAs, thereby increasing the translation and stability of the targets of such microRNAs. In this review, we discuss the emerging functions of circRNAs, including RNA transcription, splicing, turnover, and translation. We also discuss other possible facets of circRNAs that can influence their function depending on the cell context, such as circRNA abundance, subcellular localization, interacting partners (RNA, DNA, and proteins), dynamic changes in interactions following stimulation, and potential circRNA translation. The ensuing changes in gene expression patterns elicited by circRNAs are proposed to drive key cellular processes, such as cell proliferation, differentiation, and survival, that govern health and disease.For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-09-09T01:39:05.378984-05:
      DOI: 10.1002/wrna.1386
  • Extracellular RNA in aging
    • Authors: Douglas F. Dluzen; Nicole Noren Hooten, Michele K. Evans
      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.
      PubDate: 2016-08-17T00:10:38.71634-05:0
      DOI: 10.1002/wrna.1385
  • Roles of long noncoding RNAs in chromosome domains
    • Authors: Saori Tomita; Mohamed Osama Ali Abdalla, Saori Fujiwara, Tatsuro Yamamoto, Hirotaka Iwase, Mitsuyoshi Nakao, Noriko Saitoh
      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.
      PubDate: 2016-08-03T23:40:50.241484-05:
      DOI: 10.1002/wrna.1384
  • The nuts and bolts of the endogenous spliceosome
    • Authors: Ruth Sperling
      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).
      PubDate: 2016-07-27T21:10:43.72229-05:0
      DOI: 10.1002/wrna.1377
  • Modulating splicing with small molecular inhibitors of the spliceosome
    • Authors: Kerstin A. Effenberger; Veronica K. Urabe, Melissa S. Jurica
      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
      PubDate: 2016-07-21T02:20:36.563408-05:
      DOI: 10.1002/wrna.1381
  • Evolutionary clues in lncRNAs
    • Authors: Anne Nitsche; Peter F. Stadler
      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.
      PubDate: 2016-07-19T23:16:47.073791-05:
      DOI: 10.1002/wrna.1376
  • New insights into decapping enzymes and selective mRNA decay
    • Authors: Ewa Grudzien‐Nogalska; Megerditch Kiledjian
      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.
      PubDate: 2016-07-17T20:40:25.725109-05:
      DOI: 10.1002/wrna.1379
  • Transcending the prediction paradigm: novel applications of SHAPE to RNA
           function and evolution
    • Authors: Katrina M. Kutchko; Alain Laederach
      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.
      PubDate: 2016-07-10T21:30:30.939808-05:
      DOI: 10.1002/wrna.1374
  • Translating the epitranscriptome
    • Authors: Thomas Philipp Hoernes; Matthias David Erlacher
      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, N6‐methyladenosine (m6A), pseudouridine (Ψ), 5‐methylcytosine (m5C) and N1‐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.
      PubDate: 2016-06-27T01:20:25.032058-05:
      DOI: 10.1002/wrna.1375
  • The organization and regulation of mRNA–protein complexes
    • Authors: Olivia S. Rissland
      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.
      PubDate: 2016-06-21T01:55:30.5694-05:00
      DOI: 10.1002/wrna.1369
  • Posttranslational control of HuR function
    • Authors: Ioannis Grammatikakis; Kotb Abdelmohsen, Myriam Gorospe
      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.
      PubDate: 2016-06-16T01:20:31.289816-05:
      DOI: 10.1002/wrna.1372
  • The role of mRNA structure in bacterial translational regulation
    • Authors: Michelle M. Meyer
      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.
      PubDate: 2016-06-14T23:15:31.196137-05:
      DOI: 10.1002/wrna.1370
  • Hallmarks of cancer and AU‐rich elements
    • Authors: Khalid S. A. Khabar
      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.
      PubDate: 2016-06-01T22:15:30.305811-05:
      DOI: 10.1002/wrna.1368
  • Going global: the new era of mapping modifications in RNA
    • Authors: Patrick A. Limbach; Mellie June Paulines
      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.
      PubDate: 2016-06-01T21:40:34.378365-05:
      DOI: 10.1002/wrna.1367
  • RNA‐Seq methods for transcriptome analysis
    • Authors: Radmila Hrdlickova; Masoud Toloue, Bin Tian
      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.
      PubDate: 2016-05-19T22:00:29.408492-05:
      DOI: 10.1002/wrna.1364
  • Ribosome‐based quality control of mRNA and nascent peptides
    • Authors: Carrie L. Simms; Erica N. Thomas, Hani S. Zaher
      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.
      PubDate: 2016-05-18T22:35:31.244382-05:
      DOI: 10.1002/wrna.1366
  • Issue information
    • Pages: 723 - 725
      PubDate: 2016-10-14T21:06:52.106943-05:
      DOI: 10.1002/wrna.1306
  • Small molecules targeting viral RNA
    • Authors: Thomas Hermann
      First page: 726
      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.
      PubDate: 2016-06-16T00:20:33.010493-05:
      DOI: 10.1002/wrna.1373
  • Expected and unexpected features of protein‐binding RNA aptamers
    • Authors: Nils Bjerregaard; Peter A. Andreasen, Daniel M. Dupont
      First page: 744
      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.
      PubDate: 2016-05-12T23:50:45.182374-05:
      DOI: 10.1002/wrna.1360
  • Exosome‐mediated small RNA delivery for gene therapy
    • Authors: Yu Zhou; Geyu Zhou, Chenfei Tian, Waner Jiang, Ling Jin, Chenyu Zhang, Xi Chen
      First page: 758
      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.
      PubDate: 2016-05-16T00:45:28.709608-05:
      DOI: 10.1002/wrna.1363
  • Translational regulation in blood stages of the malaria parasite
           Plasmodium spp.: systems‐wide studies pave the way
    • Authors: Shruthi Sridhar Vembar; Dorothea Droll, Artur Scherf
      First page: 772
      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.
      PubDate: 2016-05-26T20:55:32.920088-05:
      DOI: 10.1002/wrna.1365
  • Advances in the characterization of RNA‐binding proteins
    • Authors: Domenica Marchese; Natalia Sanchez de Groot, Nieves Lorenzo Gotor, Carmen Maria Livi, Gian G. Tartaglia
      First page: 793
      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.
      PubDate: 2016-08-08T21:56:43.363968-05:
      DOI: 10.1002/wrna.1378
  • Identifying fusion transcripts using next generation sequencing
    • Authors: Shailesh Kumar; Sundus Khalid Razzaq, Angie Duy Vo, Mamta Gautam, Hui Li
      First page: 811
      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.
      PubDate: 2016-08-02T21:40:45.504217-05:
      DOI: 10.1002/wrna.1382
  • Virus‐derived small RNAs: molecular footprints of
           host–pathogen interactions
    • Authors: Eric Roberto Guimarães Rocha Aguiar; Roenick Proveti Olmo, João Trindade Marques
      First page: 824
      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.
      PubDate: 2016-05-12T02:51:18.82126-05:0
      DOI: 10.1002/wrna.1361
  • mRNA methylation by NSUN2 in cell proliferation
    • Authors: Wengong Wang
      First page: 838
      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.
      PubDate: 2016-07-22T01:16:29.38311-05:0
      DOI: 10.1002/wrna.1380
  • Fluorophore‐binding RNA aptamers and their applications
    • Authors: Elena V. Dolgosheina; Peter J. Unrau
      First page: 843
      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.
      PubDate: 2016-08-08T09:51:40.564355-05:
      DOI: 10.1002/wrna.1383
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