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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  [1605 journals]
  • Bioinformatic tools for analysis of CLIP ribonucleoprotein data
    • Authors: Supriyo De; Myriam Gorospe
      Abstract: Investigating the interactions of RNA-binding proteins (RBPs) with RNAs is a complex task for molecular and computational biologists. The molecular biology techniques and the computational approaches to understand RBP–RNA (or ribonucleoprotein, RNP) interactions have advanced considerably over the past few years and numerous and diverse software tools have been developed to analyze these data. Accordingly, laboratories interested in RNP biology face the challenge of choosing adequately among the available software tools those that best address the biological problem they are studying. Here, we focus on state-of-the-art molecular biology techniques that employ crosslinking and immunoprecipitation (CLIP) of an RBP to study and map RNP interactions. We review the different software tools and databases available to analyze the most widely used CLIP methods, HITS-CLIP, PAR-CLIP, and iCLIP.Overview of CLIP-Seq analysis, from the isolation of cellular RNPs to the identification and analysis of RBP-bound RNA segments using the bioinformatic tools described in this review.
      PubDate: 2016-12-23T00:31:16.732754-05:
      DOI: 10.1002/wrna.1404
       
  • The exon junction complex: a lifelong guardian of mRNA fate
    • Authors: Lauren A. Woodward; Justin W. Mabin, Pooja Gangras, Guramrit Singh
      Abstract: During messenger RNA (mRNA) biogenesis and processing in the nucleus, many proteins are imprinted on mRNAs assembling them into messenger ribonucleoproteins (mRNPs). Some of these proteins remain stably bound within mRNPs and have a long-lasting impact on their fate. One of the best-studied examples is the exon junction complex (EJC), a multiprotein complex deposited primarily 24 nucleotides upstream of exon–exon junctions as a consequence of pre-mRNA splicing. The EJC maintains a stable, sequence-independent, hold on the mRNA until its removal during translation in the cytoplasm. Acting as a molecular shepherd, the EJC travels with mRNA across the cellular landscape coupling pre-mRNA splicing to downstream, posttranscriptional processes such as mRNA export, mRNA localization, translation, and nonsense-mediated mRNA decay (NMD). In this review, we discuss our current understanding of the EJC’s functions during these processes, and expound its newly discovered functions (e.g., pre-mRNA splicing). Another focal point is the recently unveiled in vivo EJC interactome, which has shed new light on the EJC's location on the spliced RNAs and its intimate relationship with other mRNP components. We summarize new strides being made in connecting the EJC’s molecular function with phenotypes, informed by studies of human disorders and model organisms. The progress toward understanding EJC functions has revealed, in its wake, even more questions, which are discussed throughout.For further resources related to this article, please visit the WIREs website.Assembly, structure, and function of the Exon Junction Complex (EJC).
      PubDate: 2016-12-23T00:06:42.359406-05:
      DOI: 10.1002/wrna.1411
       
  • Issue information
    • PubDate: 2016-12-22T01:21:50.24293-05:0
      DOI: 10.1002/wrna.1387
       
  • Cover Image, Volume 8, Issue 1
    • Authors: Ruth Sperling
      Abstract: The cover image, by Ruth Sperling, is based on the Advanced Review The nuts and bolts of the endogenous spliceosome,
      DOI : 10.1002/wrna.1377.The cover image, by Ruth Sperling, is based on the Advanced Review The nuts and bolts of the endogenous spliceosome,
      DOI : 10.1002/wrna.1377.
      PubDate: 2016-12-22T01:21:50.195473-05:
       
  • Long noncoding RNAs in the p53 network
    • Authors: Ritu Chaudhary; Ashish Lal
      Abstract: The tumor-suppressor protein p53 is activated in response to numerous cellular stresses including DNA damage. p53 functions primarily as a sequence-specific transcription factor that controls the expression of hundreds of protein-coding genes and noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). While the role of protein-coding genes and miRNAs in mediating the effects of p53 has been extensively studied, the physiological function and molecular mechanisms by which p53-regulated lncRNAs act is beginning to be understood. In this review, we discuss recent studies on lncRNAs that are directly or indirectly regulated by p53 and how they contribute to the biological outcomes of p53 activation.For further resources related to this article, please visit the WIREs website.DNA damage is known to induce cell cycle arrest, apoptosis and senescence via protein-coding genes that are direct targets of p53. In addition, noncoding RNAs such as miRNAs (e.g., miR-34a) and lncRNAs (e.g., PANDA, Pint, LincRNA-p21and LED) mediate these effects of p53 by regulating a subset of p53 targets that control cell cycle arrest, apoptosis and senescence.
      PubDate: 2016-12-19T02:27:08.266471-05:
      DOI: 10.1002/wrna.1410
       
  • Current progress on microRNAs-based therapeutics in neurodegenerative
           diseases
    • Authors: Patrícia Pereira; João A. Queiroz, Ana Figueiras, Fani Sousa
      Abstract: MicroRNAs (miRNAs)-based therapy has recently emerged as a promising strategy in the treatments of neurodegenerative diseases. Thus, in this review, the most recent and important challenges and advances on the development of miRNA therapeutics for brain targeting are discussed. In particular, this review highlights current knowledge and progress in the field of manufacturing, recovery, isolation, purification, and analysis of these therapeutic oligonucleotides. Finally, the available miRNA delivery systems are reviewed and an analysis is presented in what concerns to the current challenges that have to be addressed to ensure their specificity and efficacy. Overall, it is intended to provide a perspective on the future of miRNA-based therapeutics, focusing the biotechnological approach to obtain miRNAs.For further resources related to this article, please visit the WIREs website.Barriers to in vivo microRNAs delivery
      PubDate: 2016-11-24T00:46:10.722175-05:
      DOI: 10.1002/wrna.1409
       
  • Perfect timing: splicing and transcription rates in living cells
    • Authors: Tara Alpert; Lydia Herzel, Karla M. Neugebauer
      Abstract: An important step toward understanding gene regulation is the elucidation of the time necessary for the completion of individual steps. Measurement of reaction rates can reveal potential nodes for regulation. For example, measurements of in vivo transcription elongation rates reveal regulation by DNA sequence, gene architecture, and chromatin. Pre-mRNA splicing is regulated by transcription elongation rates and vice versa, yet the rates of RNA processing reactions remain largely elusive. Since the 1980s, numerous model systems and approaches have been used to determine the precise timing of splicing in vivo. Because splicing can be co-transcriptional, the position of Pol II when splicing is detected has been used as a proxy for time by some investigators. In addition to these ‘distance-based’ measurements, ‘time-based’ measurements have been possible through live cell imaging, metabolic labeling of RNA, and gene induction. Yet splicing rates can be convolved by the time it takes for transcription, spliceosome assembly and spliceosome disassembly. The variety of assays and systems used has, perhaps not surprisingly, led to reports of widely differing splicing rates in vivo. Recently, single molecule RNA-seq has indicated that splicing occurs more quickly than previously deduced. Here we comprehensively review these findings and discuss evidence that splicing and transcription rates are closely coordinated, facilitating the efficiency of gene expression. On the other hand, introduction of splicing delays through as yet unknown mechanisms provide opportunity for regulation. More work is needed to understand how cells optimize the rates of gene expression for a range of biological conditions.For further resources related to this article, please visit the WIREs website.Schematic showing the progress of RNA polymerase II (Pol II) along the length of gene containing an intron (blue, top panel). The nascent RNA undergoes co-transcriptional, capping splicing and polyadenylation cleavage. The association of spliceosomal components with the ends of the intron is represented by the presence of the red balls, and the exon-exon junction is marked by a line. This review revisits a multitude of methods that measure in vivo splicing rates with respect to kilobasepair distance (ruler) from the 3' splice site (SS) or in units of time (clock, lower panel).
      PubDate: 2016-11-21T21:55:31.10735-05:0
      DOI: 10.1002/wrna.1401
       
  • Unwinding the twister ribozyme: from structure to mechanism
    • Authors: Jennifer Gebetsberger; Ronald Micura
      Abstract: The twister ribozyme motif has been identified by bioinformatic means very recently. Currently, four crystal structures with ordered active sites together with a series of chemical and biochemical data provide insights into how this RNA accomplishes its efficient self-cleavage. Of particular interest for a mechanistic proposal are structural distinctions observed in the active sites that concern the conformation of the U-A cleavage site dinucleotide (in-line alignment of the attacking 2′-O nucleophile to the to-be-cleaved PO5′ bond versus suboptimal alignments) as well as the presence/absence of Mg2+ ions at the scissile phosphate. All structures support the notion that an active site guanine and the conserved adenine at the cleavage site are important contributors to cleavage chemistry, likely being involved in general acid base catalysis. Evidence for innersphere coordination of a Mg2+ ion to the pro-S nonbridging oxygen of the scissile phosphate stems from two of the four crystal structures. Together with the finding of thio/rescue effects for phosphorothioate substrates, this suggests the participation of divalent ions in the overall catalytic strategy employed by twister ribozymes. In this context, it is notable that twister retains wild-type activity when the phylogenetically conserved stem P1 is deleted, able to cleave a single nucleotide only.For further resources related to this article, please visit the WIREs website.Small self-cleaving ribozymes perform the same internal transesterification reaction although possessing distinct folds and active sites. They can employ four strategies to catalyze phosphordiester cleavage indicated by colored arrows (left panel; for explanation see main text). Close-up view of the env22 twister ribozyme active site (right panel; pdb: 4RGE). The to-be-cleaved dinucleotide unit is shown in yellow. Guanine (G48) and adenine (A6) together with Mg2+ are likely the key players for twister ribozyme catalysis.
      PubDate: 2016-11-14T01:35:38.417735-05:
      DOI: 10.1002/wrna.1402
       
  • Regulation of mRNA turnover in cystic fibrosis lung disease
    • Authors: Roopa Biswas; Parameet Kumar, Harvey B. Pollard
      Abstract: Cystic fibrosis (CF) is an autosomal recessive disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, F508del-CFTR being the most frequent mutation. The CF lung is characterized by a hyperinflammatory phenotype and is regulated by multiple factors that coordinate its pathophysiology. In CF the expression of CFTR as well as proinflammatory genes are regulated at the level of messenger RNA (mRNA) stability, which subsequently affect translation. These mechanisms are mediated by inflammatory RNA-binding proteins as well as small endogenous noncoding microRNAs, in coordination with cellular signaling pathways. These regulatory factors exhibit altered expression and function in vivo in the CF lung, and play a key role in the pathophysiology of CF lung disease. In this review, we have described the role of mRNA stability and associated regulatory mechanisms in CF lung disease.For further resources related to this article, please visit the WIREs website.Various trans-factors (RNA-binding proteins and/or miRNAs) interact with cis-elements on the mRNA 3′-UTR sequences and regulate the expression of F508del-CFTR and proinflammatory chemokine and cytokine genes (like IL-8 and IL-6) in the cystic fibrosis airway. The concerted effect of these factors and the resulting complex regulatory network regulate the CF disease phenotype.
      PubDate: 2016-11-13T20:55:23.36762-05:0
      DOI: 10.1002/wrna.1408
       
  • How to understand atomistic molecular dynamics simulations of RNA and
           protein–RNA complexes'
    • Authors: Jiří Šponer; Miroslav Krepl, Pavel Banáš, Petra Kührová, Marie Zgarbová, Petr Jurečka, Marek Havrila, Michal Otyepka
      Abstract: We provide a critical assessment of explicit-solvent atomistic molecular dynamics (MD) simulations of RNA and protein/RNA complexes, written primarily for non-specialists with an emphasis to explain the limitations of MD. MD simulations can be likened to hypothetical single-molecule experiments starting from single atomistic conformations and investigating genuine thermal sampling of the biomolecules. The main advantage of MD is the unlimited temporal and spatial resolution of positions of all atoms in the simulated systems. Fundamental limitations are the short physical time-scale of simulations, which can be partially alleviated by enhanced-sampling techniques, and the highly approximate atomistic force fields describing the simulated molecules. The applicability and present limitations of MD are demonstrated on studies of tetranucleotides, tetraloops, ribozymes, riboswitches and protein/RNA complexes. Wisely applied simulations respecting the approximations of the model can successfully complement structural and biochemical experiments.For further resources related to this article, please visit the WIREs website.MD simulations allow to study structural dynamics, flexibility, hydration, ion-binding, base substitutions and other properties based on available atomistic experimental structures of RNAs and protein-RNA complexes.
      PubDate: 2016-11-10T21:05:36.086057-05:
      DOI: 10.1002/wrna.1405
       
  • Posttranscriptional coordination of splicing and miRNA biogenesis in
           plants
    • Authors: Agata Stepien; Katarzyna Knop, Jakub Dolata, Michal Taube, Mateusz Bajczyk, Maria Barciszewska-Pacak, Andrzej Pacak, Artur Jarmolowski, Zofia Szweykowska-Kulinska
      Abstract: MicroRNAs (miRNAs) are short, single-stranded, noncoding RNAs that play a crucial role in basic physiological and morphological processes and in response to various stresses in eukaryotic organisms. However, the miRNA biogenesis, which is based on the action of complex protein machinery, varies between plants and animals, with the differences largely concerning the location of the process, the protein composition of the microprocessor, the mechanism of miRNA action on mRNA target, and the miRNA gene (MIR) structure. Roughly half of known Arabidopsis MIRs contain introns, and 29 miRNAs are encoded within the introns of host genes. Selection of alternative transcription start sites, alternative splice sites (SSs), and polyadenylation sites has been identified within miRNA primary transcripts (pri-miRNAs), and such variety is essential for the production and fine-tuning of miRNA levels. For example, the posttranscriptional processing of intron-containing pri-miRNAs involves the action of additional RNA metabolism machineries, such as the spliceosome and polyadenylation machinery, and to a large extent is based on direct communication between SERRATE (one of the core components of the plant microprocessor) and U1 snRNP auxiliary proteins. Moreover, the position of the miRNA stem–loop structure relative to the closest active 5′SS is essential for the miRNA production efficiency. Indeed, it is highly probable that this pre-miRNA location affects recruitment of the microprocessor to pri-miRNAs and therefore influences miRNA maturation and target mRNA regulation. Such complicated crosstalk between several machineries is important for a proper miRNA-connected response to biotic and abiotic stresses, ensuring plant survival in a changing environment.For further resources related to this article, please visit the WIREs website.The crosstalk between transcription, splicing, polyadenylation and miRNA biogenesis machineries in the regulation of plant miRNA level.
      PubDate: 2016-11-09T15:32:14.553927-05:
      DOI: 10.1002/wrna.1403
       
  • New evolutionary insights into the non-enzymatic origin of RNA oligomers
    • Authors: Judit E. Šponer; Jiří Šponer, Ernesto Di Mauro
      Abstract: We outline novel findings on the non-enzymatic polymerization of nucleotides under plausible prebiotic conditions and on the spontaneous onset of informational complexity in the founding molecule, RNA. We argue that the unique ability of 3′, 5′ cyclic guanosine monophosphate to form stacked architectures and polymerize in a self-sustained manner suggests that this molecule may serve as the ‘seed of life’ from which all self-replicating oligonucleotides can be derived via a logically complete sequence of simple events.For further resources related to this article, please visit the WIREs website.The formamide-based funnel model we present in this work outlines a straightforward path from primordial molecules to catalytically active oligonucleotides.
      PubDate: 2016-10-26T21:55:30.648078-05:
      DOI: 10.1002/wrna.1400
       
  • Developmental regulation of RNA processing by Rbfox proteins
    • Authors: John G. Conboy
      Abstract: The Rbfox genes encode an ancient family of sequence-specific RNA binding proteins (RBPs) that are critical developmental regulators in multiple tissues including skeletal muscle, cardiac muscle, and brain. The hallmark of Rbfox proteins is a single high-affinity RRM domain, highly conserved from insects to humans, that binds preferentially to UGCAUG motifs at diverse regulatory sites in pre-mRNA introns, mRNA 3’UTRs, and pre-miRNAs hairpin structures. Versatile regulatory circuits operate on Rbfox pre-mRNA and mRNA to ensure proper expression of Rbfox1 protein isoforms, which then act on the broader transcriptome to regulate alternative splicing networks, mRNA stability and translation, and microRNA processing. Complex Rbfox expression is encoded in large genes encompassing multiple promoters and alternative splicing options that govern spatiotemporal expression of structurally distinct and tissue-specific protein isoforms with different classes of RNA targets. Nuclear Rbfox1 is a candidate master regulator that binds intronic UGCAUG elements to impact splicing efficiency of target alternative exons, many in transcripts for other splicing regulators. Tissue-specificity of Rbfox-mediated alternative splicing is executed by combinatorial regulation through the integrated activity of Rbfox proteins and synergistic or antagonistic splicing factors. Studies in animal models show that Rbfox1-related genes are critical for diverse developmental processes including germ cell differentiation and memory in Drosophila, neuronal migration and function in mouse brain, myoblast fusion and skeletal muscle function, and normal heart function. Finally, genetic and biochemical evidence suggest that aberrations in Rbfox-regulated circuitry are risk factors for multiple human disorders, especially neurodevelopmental disorders including epilepsy and autism, and cardiac hypertrophy.For further resources related to this article, please visit the WIREs website.Rbfox binding sites associate with multiple RNA processing pathways. Nuclear binding sites influence pre-mRNA processing and microRNA processing, activities that may be titrated by sequestration of Rbfox at SNORD116 binding sites. Cytoplasmic Rbfox binds 3'UTR sequences to influence mRNA stability and translation.
      PubDate: 2016-10-17T00:16:39.092543-05:
      DOI: 10.1002/wrna.1398
       
  • 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
           fields
    • 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
       
 
 
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