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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  [1597 journals]
  • RNA‐binding proteins in eye development and disease: implication of
           conserved RNA granule components
    • Authors: Soma Dash; Archana D. Siddam, Carrie E. Barnum, Sarath Chandra Janga, Salil A. Lachke
      Abstract: The molecular biology of metazoan eye development is an area of intense investigation. These efforts have led to the surprising recognition that although insect and vertebrate eyes have dramatically different structures, the orthologs or family members of several conserved transcription and signaling regulators such as Pax6, Six3, Prox1, and Bmp4 are commonly required for their development. In contrast, our understanding of posttranscriptional regulation in eye development and disease, particularly regarding the function of RNA‐binding proteins (RBPs), is limited. We examine the present knowledge of RBPs in eye development in the insect model Drosophila as well as several vertebrate models such as fish, frog, chicken, and mouse. Interestingly, of the 42 RBPs that have been investigated for their expression or function in vertebrate eye development, 24 (~60%) are recognized in eukaryotic cells as components of RNA granules such as processing bodies, stress granules, or other specialized ribonucleoprotein (RNP) complexes. We discuss the distinct developmental and cellular events that may necessitate potential RBP/RNA granule‐associated RNA regulon models to facilitate posttranscriptional control of gene expression in eye morphogenesis. In support of these hypotheses, three RBPs and RNP/RNA granule components Tdrd7, Caprin2, and Stau2 are linked to ocular developmental defects such as congenital cataract, Peters anomaly, and microphthalmia in human patients or animal models. We conclude by discussing the utility of interdisciplinary approaches such as the bioinformatics tool iSyTE (integrated Systems Tool for Eye gene discovery) to prioritize RBPs for deriving posttranscriptional regulatory networks in eye development and disease. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-05-01T19:55:04.612954-05:
      DOI: 10.1002/wrna.1355
  • Dual roles of DNA repair enzymes in RNA biology/post‐transcriptional
    • 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
  • Cover Image, Volume 7, Issue 3
    • Authors: Bonnie A. McNeil; Cameron Semper, Steven Zimmerly
      Abstract: The cover image, by Steven Zimmerly et al., is based on the Advanced Review Group II introns: versatile ribozymes and retroelements,
      DOI : 10.1002/wrna.1339. The cover image, by Steven Zimmerly et al., is based on the Advanced Review Group II introns: versatile ribozymes and retroelements,
      DOI : 10.1002/wrna.1339.
      PubDate: 2016-04-20T21:08:58.325719-05:
  • SAXS studies of RNA: structures, dynamics, and interactions with partners
    • Authors: Yujie Chen; Lois Pollack
      Abstract: Small‐angle X‐ray scattering, SAXS, is a powerful and easily employed experimental technique that provides solution structures of macromolecules. The size and shape parameters derived from SAXS provide global structural information about these molecules in solution and essentially complement data acquired by other biophysical methods. As applied to protein systems, SAXS is a relatively mature technology: sophisticated tools exist to acquire and analyze data, and to create structural models that include dynamically flexible ensembles. Given the expanding appreciation of RNA’s biological roles, there is a need to develop comparable tools to characterize solution structures of RNA, including its interactions with important biological partners. We review the progress toward achieving this goal, focusing on experimental and computational innovations. The use of multiphase modeling, absolute calibration and contrast variation methods, among others, provides new and often unique ways of visualizing this important biological molecule and its essential partners: ions, other RNAs, or proteins. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-04-12T20:10:59.35032-05:0
      DOI: 10.1002/wrna.1349
  • 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
    • 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
  • The reciprocal regulation between splicing and 3′‐end
    • Authors: Daisuke Kaida
      Abstract: Most eukaryotic precursor mRNAs are subjected to RNA processing events, including 5′‐end capping, splicing and 3′‐end processing. These processing events were historically studied independently; however, since the early 1990s tremendous efforts by many research groups have revealed that these processing factors interact with each other to control each other's functions. U1 snRNP and its components negatively regulate polyadenylation of precursor mRNAs. Importantly, this function is necessary for protecting the integrity of the transcriptome and for regulating gene length and the direction of transcription. In addition, physical and functional interactions occur between splicing factors and 3′‐end processing factors across the last exon. These interactions activate or inhibit splicing and 3′‐end processing depending on the context. Therefore, splicing and 3′‐end processing are reciprocally regulated in many ways through the complex protein–protein interaction network. Although interesting questions remain, future studies will illuminate the molecular mechanisms underlying the reciprocal regulation. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-03-28T01:00:42.380134-05:
      DOI: 10.1002/wrna.1348
  • mRNA trans‐splicing in gene therapy for genetic diseases
    • Abstract: Spliceosome‐mediated RNA trans‐splicing, or SMaRT, is a promising strategy to design innovative gene therapy solutions for currently intractable genetic diseases. SMaRT relies on the correction of mutations at the post‐transcriptional level by modifying the mRNA sequence. To achieve this, an exogenous RNA is introduced into the target cell, usually by means of gene transfer, to induce a splice event in trans between the exogenous RNA and the target endogenous pre‐mRNA. This produces a chimeric mRNA composed partly of exons of the latter, and partly of exons of the former, encoding a sequence free of mutations. The principal challenge of SMaRT technology is to achieve a reaction as complete as possible, i.e., resulting in 100% repairing of the endogenous mRNA target. The proof of concept of SMaRT feasibility has already been established in several models of genetic diseases caused by recessive mutations. In such cases, in fact, the repair of only a portion of the mutant mRNA pool may be sufficient to obtain a significant therapeutic effect. However in the case of dominant mutations, the target cell must be freed from the majority of mutant mRNA copies, requiring a highly efficient trans‐splicing reaction. This likely explains why only a few examples of SMaRT approaches targeting dominant mutations are reported in the literature. In this review, we explain in details the mechanism of trans‐splicing, review the different strategies that are under evaluation to lead to efficient trans‐splicing, and discuss the advantages and limitations of SMaRT. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-03-28T00:45:40.876503-05:
      DOI: 10.1002/wrna.1347
  • Emerging functions of the Quaking RNA‐binding proteins and link to
           human diseases
    • Abstract: RNA‐binding proteins (RBPs) are essential players in RNA metabolism including key cellular processes from pre‐mRNA splicing to mRNA translation. The K homology‐type QUAKING RBP is emerging as a vital factor for oligodendrocytes, monocytes/macrophages, endothelial cell, and myocyte function. Interestingly, the qkI gene has now been identified as the culprit gene for a patient with intellectual disabilities and is translocated in a pediatric ganglioglioma as a fusion protein with MYB. In this review, we will focus on the emerging discoveries of the QKI proteins as well as highlight the recent advances in understanding the role of QKI in human disease pathology including myelin disorders, schizophrenia and cancer. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-03-14T18:55:47.213363-05:
      DOI: 10.1002/wrna.1344
  • New insights from cluster analysis methods for RNA secondary structure
    • Authors: Emily Rogers; Christine Heitsch
      Abstract: A widening gap exists between the best practices for RNA secondary structure prediction developed by computational researchers and the methods used in practice by experimentalists. Minimum free energy predictions, although broadly used, are outperformed by methods which sample from the Boltzmann distribution and data mine the results. In particular, moving beyond the single structure prediction paradigm yields substantial gains in accuracy. Furthermore, the largest improvements in accuracy and precision come from viewing secondary structures not at the base pair level but at lower granularity/higher abstraction. This suggests that random errors affecting precision and systematic ones affecting accuracy are both reduced by this ‘fuzzier’ view of secondary structures. Thus experimentalists who are willing to adopt a more rigorous, multilayered approach to secondary structure prediction by iterating through these levels of granularity will be much better able to capture fundamental aspects of RNA base pairing. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-03-11T21:51:06.805049-05:
      DOI: 10.1002/wrna.1334
  • A structurally plastic ribonuceloprotein complex mediates
           post‐transcriptional gene regulation in HIV‐1
    • Authors: Jason D. Fernandes; David S. Booth, Alan D. Frankel
      Abstract: HIV replication requires the nuclear export of essential, intron‐containing viral RNAs. To facilitate export, HIV encodes the viral accessory protein Rev which binds unspliced and partially spliced viral RNAs and creates a ribonucleoprotein complex that recruits the cellular Chromosome maintenance factor 1 export machinery. Exporting RNAs in this manner bypasses the necessity for complete splicing as a prerequisite for mRNA export, and allows intron‐containing RNAs to reach the cytoplasm intact for translation and virus packaging. Recent structural studies have revealed that this entire complex exhibits remarkable plasticity at many levels of organization, including RNA folding, protein–RNA recognition, multimer formation, and host factor recruitment. In this review, we explore each aspect of plasticity from structural, functional, and possible therapeutic viewpoints. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-03-01T01:12:26.43995-05:0
      DOI: 10.1002/wrna.1342
  • Group II introns: versatile ribozymes and retroelements
    • Authors: Bonnie A. McNeil; Cameron Semper, Steven Zimmerly
      Abstract: Group II introns are catalytic RNAs (ribozymes) and retroelements found in the genomes of bacteria, archaebacteria, and organelles of some eukaryotes. The prototypical retroelement form consists of a structurally conserved RNA and a multidomain reverse transcriptase protein, which interact with each other to mediate splicing and mobility reactions. A wealth of biochemical, cross‐linking, and X‐ray crystal structure studies have helped to reveal how the two components cooperate to carry out the splicing and mobility reactions. In addition to the standard retroelement form, group II introns have evolved into derivative forms by either losing specific splicing or mobility characteristics, or becoming functionally specialized. Of particular interest are the eukaryotic derivatives—the spliceosome, spliceosomal introns, and non‐LTR retroelements—which together make up approximately half of the human genome. On a practical level, the properties of group II introns have been exploited to develop group II intron‐based biotechnological tools. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-02-15T00:17:04.038803-05:
      DOI: 10.1002/wrna.1339
  • Riboregulation of bacterial and archaeal transposition
    • Authors: Michael J. Ellis; David B. Haniford
      Abstract: The coexistence of transposons with their hosts depends largely on transposition levels being tightly regulated to limit the mutagenic burden associated with frequent transposition. For ‘DNA‐based’ (class II) bacterial transposons there is growing evidence that regulation through small noncoding RNAs and/or the RNA‐binding protein Hfq are prominent mechanisms of defense against transposition. Recent transcriptomics analyses have identified many new cases of antisense RNAs (asRNA) that potentially could regulate the expression of transposon‐encoded genes giving the impression that asRNA regulation of DNA‐based transposons is much more frequent than previously thought. Hfq is a highly conserved bacterial protein that plays a central role in posttranscriptional gene regulation and stress response pathways in many bacteria. Three different mechanisms for Hfq‐directed control of bacterial transposons have been identified to date highlighting the versatility of this protein as a regulator of bacterial transposons. There is also evidence emerging that some DNA‐based transposons encode RNAs that could regulate expression of host genes. In the case of IS200, which appears to have lost its ability to transpose, contributing a regulatory RNA to its host could account for the persistence of this mobile element in a wide range of bacterial species. It remains to be seen how prevalent these transposon‐encoded RNA regulators are, but given the relatively large amount of intragenic transcription in bacterial genomes, it would not be surprising if new examples are forthcoming. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-02-04T19:59:34.032499-05:
      DOI: 10.1002/wrna.1341
  • RNA recognition by Roquin in posttranscriptional gene regulation
    • Authors: Andreas Schlundt; Dierk Niessing, Vigo Heissmeyer, Michael Sattler
      Abstract: Posttranscriptional regulation of gene expression plays a central role in the initiation of innate and adaptive immune responses. This is exemplified by the protein Roquin, which has attracted great interest during the past decade owing to its ability to prevent autoimmunity. Roquin controls T‐cell activation and T helper cell differentiation by limiting the induced expression of costimulatory receptors on the surface of T cells. It does so by recognizing cis regulatory RNA‐hairpin elements in the 3′ UTR of target transcripts via its ROQ domain—a novel RNA‐binding fold—and triggering their degradation through recruitment of factors that mediate deadenylation and decapping. Recent structural studies have revealed molecular details of the recognition of RNA hairpin structures by the ROQ domain. Surprisingly, it was found that Roquin mainly relies on shape‐specific recognition of the RNA. This observation implies that a much broader range of RNA motifs could interact with the protein, but it also complicates systematic searches for novel mRNA targets of Roquin. Thus, large‐scale approaches, such as crosslinking and immunoprecipitation or systematic evolution of ligands by exponential enrichment experiments coupled with next‐generation sequencing, will be required to identify the complete spectrum of its target RNAs. Together with structural analyses of their binding modes, this will enable us to unravel the intricate complexity of 3′ UTR regulation by Roquin and other trans‐acting factors. Here, we review our current understanding of Roquin–RNA interactions and their role for Roquin function. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-02-04T19:32:27.826011-05:
      DOI: 10.1002/wrna.1333
  • siRNA and RNAi optimization
    • Authors: Adele Alagia; Ramon Eritja
      Abstract: The discovery and examination of the posttranscriptional gene regulatory mechanism known as RNA interference (RNAi) contributed to the identification of small interfering RNA (siRNA) and the comprehension of its enormous potential for clinical purposes. Theoretically, the ability of specific target gene downregulation makes the RNAi pathway an appealing solution for several diseases. Despite numerous hurdles resulting from the inherent properties of siRNA molecule and proper delivery to the target tissue, more than 50 RNA‐based drugs are currently under clinical testing. In this work, we analyze the recent literature in the optimization of siRNA molecules. In detail, we focused on describing the most recent advances of siRNA field aimed at optimize siRNA pharmacokinetic properties. Special attention has been given in describing the impact of RNA modifications in the potential off‐target effects (OTEs) such as saturation of the RNAi machinery, passenger strand‐mediated silencing, immunostimulation, and miRNA‐like OTEs as well as to recent developments on the delivery issue. The novel delivery systems and modified siRNA provide significant steps toward the development of reliable siRNA molecules for therapeutic use. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-02-02T19:42:35.892644-05:
      DOI: 10.1002/wrna.1337
  • The Ccr4‐Not complex is a key regulator of eukaryotic gene
    • Authors: Martine A. Collart
      Abstract: The Ccr4‐Not complex is a multisubunit complex present in all eukaryotes that contributes to regulate gene expression at all steps, from production of messenger RNAs (mRNAs) in the nucleus to their degradation in the cytoplasm. In the nucleus it influences the post‐translational modifications of the chromatin template that has to be remodeled for transcription, it is present at sites of transcription and associates with transcription factors as well as with the elongating polymerase, it interacts with the factors that prepare the new transcript for export to the cytoplasm and finally is important for nuclear quality control and influences mRNA export. In the cytoplasm it is present in polysomes where mRNAs are translated and in RNA granules where mRNAs will be redirected upon inhibition of translation. It influences mRNA translatability, and is needed during translation, on one hand for co‐translational protein interactions and on the other hand to preserve translation that stalls. It is one of the relevant players during co‐translational quality control. It also interacts with factors that will repress translation or induce mRNA decapping when recruited to the translating template. Finally, Ccr4‐Not carries deadenylating enzymes and is a key player in mRNA decay, generic mRNA decay that follows normal translation termination, co‐translational mRNA decay of transcripts on which the ribosomes stall durably or which carry a non‐sense mutation and finally mRNA decay that is induced by external signaling for a change in genetic programming. Ccr4‐Not is a master regulator of eukaryotic gene expression. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-01-29T00:37:23.76017-05:0
      DOI: 10.1002/wrna.1332
  • Prohead RNA: a noncoding viral RNA of novel structure and function
    • Authors: Alyssa C. Hill; Laura E. Bartley, Susan J. Schroeder
      Abstract: Prohead RNA (pRNA) is an essential component of the powerful Φ29‐like bacteriophage DNA packaging motor. However, the specific role of this unique RNA in the Φ29 packaging motor remains unknown. This review examines pRNA as a noncoding RNA of novel structure and function. In order to highlight the reasons for exploring the structure and function of pRNA, we (1) provide an overview of Φ29‐like bacteriophage and the Φ29 DNA packaging motor, including putative motor mechanisms and structures of its component parts; (2) discuss pRNA structure and possible roles for pRNA in the Φ29 packaging motor; (3) summarize pRNA self‐assembly; and (4) describe the prospective therapeutic applications of pRNA. Many questions remain to be answered in order to connect what is currently known about pRNA structure to its novel function in the Φ29 packaging motor. The knowledge gained from studying the structure, function, and sequence variation in pRNA will help develop tools to better navigate the conformational landscapes of RNA. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-01-25T22:27:50.838468-05:
      DOI: 10.1002/wrna.1330
  • Functionalities of expressed messenger RNAs revealed from mutant
    • Abstract: Total messenger RNAs mRNAs that are produced from a given gene under a certain set of conditions include both functional and nonfunctional transcripts. The high prevalence of nonfunctional mRNAs that have been detected in cells has raised questions regarding the functional implications of mRNA expression patterns and divergences. Phenotypes that result from the mutagenesis of protein‐coding genes have provided the most straightforward descriptions of gene functions, and such data obtained from model organisms have facilitated investigations of the functionalities of expressed mRNAs. Mutant phenotype data from mouse tissues have revealed various attributes of functional mRNAs, including tissue‐specificity, strength of expression, and evolutionary conservation. In addition, the role that mRNA expression evolution plays in driving morphological evolution has been revealed from studies designed to exploit morphological and physiological phenotypes of mouse mutants. Investigations into yeast essential genes (defined by an absence of colony growth after gene deletion) have further described gene regulatory strategies that reduce protein expression noise by mediating the rates of transcription and translation. In addition to the functional significance of expressed mRNAs as described in the abovementioned findings, the functionalities of other type of RNAs (i.e., noncoding RNAs) remain to be characterized with systematic mutations and phenotyping of the DNA regions that encode these RNA molecules. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-01-07T21:26:06.192755-05:
      DOI: 10.1002/wrna.1329
  • Issue information
    • Pages: 275 - 277
      PubDate: 2016-04-20T21:08:57.65123-05:0
      DOI: 10.1002/wrna.1303
  • RNA‐binding protein hnRNPLL as a critical regulator of lymphocyte
           homeostasis and differentiation
    • Authors: Xing Chang
      First page: 295
      Abstract: RNA‐binding proteins orchestrate posttranscriptional regulation of gene expression, such as messenger RNA (mRNA) splicing, RNA stability regulation, and translation regulation. Heterogeneous nuclear RNA‐binding proteins (hnRNPs) refer to a collection of unrelated RNA‐binding proteins predominantly located in the nucleus (Han et al. Biochem J 2010, 430:379–392). Although canonical functions of hnRNPs are to promote pre‐mRNA splicing, they are involved in all the processes of RNA metabolism through recognizing specific cis‐elements on RNA (Dreyfuss et al. Annu Rev Biochem 1993, 62:289–321; Huelga et al. Cell Rep 2012, 1:167–178; Krecic and Swanson. Curr Opin Cell Biol 1999, 11:363–371). Heterogeneous nuclear RNA‐binding protein L like (hnRNPLL) is a tissue‐specific hnRNP, which was identified as a regulator of CD45RA to CD45RO switching during memory T‐cell development (Oberdoerffer et al. Science 2008, 321:686–691; Topp et al. RNA 2008, 14:2038–2049; Wu et al. Immunity 2008, 29:863–875). Since then, hnRNPLL has emerged as a critical regulator of lymphocyte homeostasis and terminal differentiation, controlling alternative splicing or expression of critical genes for the lymphocytes development (Wu et al. Immunity 2008, 29:863–875; Chang et al. Proc Natl Acad Sci USA 2015, 112:E1888–E1897). This review will summarize recent advances in understanding the functions of hnRNPLL, focusing on its biochemical functions and physiological roles in lymphocyte differentiation and homeostasis. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-01-29T00:56:58.578268-05:
      DOI: 10.1002/wrna.1335
  • Matrin3: connecting gene expression with the nuclear matrix
    • Authors: Miguel B. Coelho; Jan Attig, Jernej Ule, Christopher W.J. Smith
      First page: 303
      Abstract: As indicated by its name, Matrin3 was discovered as a component of the nuclear matrix, an insoluble fibrogranular network that structurally organizes the nucleus. Matrin3 possesses both DNA‐ and RNA‐binding domains and, consistent with this, has been shown to function at a number of stages in the life cycle of messenger RNAs. These numerous activities indicate that Matrin3, and indeed the nuclear matrix, do not just provide a structural framework for nuclear activities but also play direct functional roles in these activities. Here, we review the structure, functions, and molecular interactions of Matrin3 and of Matrin3‐related proteins, and the pathologies that can arise upon mutation of Matrin3. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-01-26T20:44:35.123416-05:
      DOI: 10.1002/wrna.1336
  • FUS‐mediated regulation of alternative RNA processing in neurons:
           insights from global transcriptome analysis
    • First page: 330
      Abstract: Fused in sarcoma (FUS) is an RNA‐binding protein that is causally associated with oncogenesis and neurodegeneration. Recently, the role of FUS in neurodegeneration has been extensively studied, because mutations in FUS are associated with amyotrophic lateral sclerosis (ALS), and the FUS protein has been identified as a major component of intracellular inclusions in neurodegenerative disorders including ALS and frontotemporal lobar degeneration. FUS is a key molecule in transcriptional regulation and RNA processing including processes such as pre‐messenger RNA (mRNA) splicing and polyadenylation. Interaction of FUS with various components of the transcription machinery, spliceosome, and the 3′‐end processing machinery has been identified. Furthermore, recent advances in high‐throughput transcriptomic profiling approaches have enabled us to determine the mechanisms of FUS‐dependent RNA processing networks at a cellular level. These analyses have revealed that depletion of FUS in neuronal cells affects alternative splicing and alternative polyadenylation of thousands of mRNAs. Gene ontology analysis has suggested that FUS‐modulated genes are implicated in neuronal functions and development. CLIP‐seq of FUS has shown that FUS is frequently clustered around these alternative sites of nascent RNA. ChIP‐seq of RNA polymerase II (RNAP II) has demonstrated that an interaction between FUS and nascent RNA downregulates local transcriptional activity of RNAP II, which is critically involved in RNA processing. Both alternative splicing and alternative polyadenylation are fundamental processes by which cells expand their transcriptomic diversity, and are particularly essential in the nervous system. Dependence of transcriptomic diversity on FUS makes the nervous system vulnerable to neurodegeneration, when FUS is functionally compromised. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-01-28T20:42:28.196436-05:
      DOI: 10.1002/wrna.1338
  • Small RNAs: essential regulators of gene expression and defenses against
           environmental stresses in plants
    • First page: 356
      Abstract: Eukaryotic genomes produce thousands of diverse small RNAs (smRNAs), which play vital roles in regulating gene expression in all conditions, including in survival of biotic and abiotic environmental stresses. SmRNA pathways intersect with most of the pathways regulating different steps in the life of a messenger RNA (mRNA), starting from transcription and ending at mRNA decay. SmRNAs function in both nuclear and cytoplasmic compartments; the regulation of mRNA stability and translation in the cytoplasm and the epigenetic regulation of gene expression in the nucleus are the main and best‐known modes of smRNA action. However, recent evidence from animal systems indicates that smRNAs and RNA interference (RNAi) also participate in the regulation of alternative pre‐mRNA splicing, one of the most crucial steps in the fast, efficient global reprogramming of gene expression required for survival under stress. Emerging evidence from bioinformatics studies indicates that a specific class of plant smRNAs, induced by various abiotic stresses, the sutr‐siRNAs, has the potential to target regulatory regions within introns and thus may act in the regulation of splicing in response to stresses. This review summarizes the major types of plant smRNAs in the context of their mechanisms of action and also provides examples of their involvement in regulation of gene expression in response to environmental cues and developmental stresses. In addition, we describe current advances in our understanding of how smRNAs function in the regulation of pre‐mRNA splicing. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-02-28T23:44:32.155696-05:
      DOI: 10.1002/wrna.1340
  • 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
    • 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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