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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  [1589 journals]
  • Viral internal ribosomal entry sites: four classes for one goal
    • Authors: Justine Mailliot; Franck Martin
      Abstract: To ensure efficient propagation, viruses need to rapidly produce viral proteins after cell entrance. Since viral genomes do not encode any components of the protein biosynthesis machinery, viral proteins must be produced by the host cell. To hi‐jack the host cellular translation, viruses use a great variety of distinct strategies. Many single‐stranded positive‐sensed RNA viruses contain so‐called internal ribosome entry sites (IRESs). IRESs are structural RNA motifs that have evolved to specific folds that recruit the host ribosomes on the viral coding sequences in order to synthesize viral proteins. In host canonical translation, recruitment of the translation machinery components is essentially guided by the 5′ cap (m7G) of mRNA. In contrast, IRESs are able to promote efficient ribosome assembly internally and in cap‐independent manner. IRESs have been categorized into four classes, based on their length, nucleotide sequence, secondary and tertiary structures, as well as their mode of action. Classes I and II require the assistance of cellular auxiliary factors, the eukaryotic intiation factors (eIF), for efficient ribosome assembly. Class III IRESs require only a subset of eIFs whereas Class IV, which are the more compact, can promote translation without any eIFs. Extensive functional and structural investigations of IRESs over the past decades have allowed a better understanding of their mode of action for viral translation. Because viral translation has a pivotal role in the infectious program, IRESs are therefore attractive targets for therapeutic purposes.For further resources related to this article, please visit the WIREs website.Viral internal ribosomal entry sites.
      PubDate: 2017-11-29T03:11:43.783085-05:
      DOI: 10.1002/wrna.1458
  • The GAIT translational control system
    • Authors: Abul Arif; Peng Yao, Fulvia Terenzi, Jie Jia, Partho Sarothi Ray, Paul L. Fox
      Abstract: The interferon (IFN)‐γ‐activated inhibitor of translation (GAIT) system directs transcript‐selective translational control of functionally related genes. In myeloid cells, IFN‐γ induces formation of a multiprotein GAIT complex that binds structural GAIT elements in the 3′‐untranslated regions (UTRs) of multiple inflammation‐related mRNAs, including ceruloplasmin and VEGF‐A, and represses their translation. The human GAIT complex is a heterotetramer containing glutamyl‐prolyl tRNA synthetase (EPRS), NS1‐associated protein 1 (NSAP1), ribosomal protein L13a (L13a), and glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH). A network of IFN‐γ‐stimulated kinases regulates recruitment and assembly of GAIT complex constituents. Activation of cyclin‐dependent kinase 5 (Cdk5), mammalian target of rapamycin complex 1 (mTORC1), and S6K1 kinases induces EPRS release from its parental multiaminoacyl tRNA synthetase complex to join NSAP1 in a ‘pre‐GAIT’ complex. Subsequently, the DAPK‐ZIPK kinase axis phosphorylates L13a, inducing release from the 60S ribosomal subunit and binding to GAPDH. The subcomplexes join to form the functional GAIT complex. Each constituent has a distinct role in the GAIT system. EPRS binds the GAIT element in target mRNAs, NSAP1 negatively regulates mRNA binding, L13a binds eIF4G to block ribosome recruitment, and GAPDH shields L13a from proteasomal degradation. The GAIT system is susceptible to genetic and condition‐specific regulation. An N‐terminus EPRS truncate is a dominant‐negative inhibitor ensuring a ‘translational trickle’ of target transcripts. Also, hypoxia and oxidatively modified lipoproteins regulate GAIT activity. Mouse models exhibiting absent or genetically modified GAIT complex constituents are beginning to elucidate the physiological role of the GAIT system, particularly in the resolution of chronic inflammation. Finally, GAIT‐like systems in proto‐chordates suggests an evolutionarily conserved role of the pathway in innate immunity.For further resources related to this article, please visit the WIREs website.IFN‐γ‐stimulated activation of the GAIT complex in human myeloid cells. A network of phosphorylation events recruits EPRS and ribosomal protein L13a to join GAPDH and NSAP1 to form the functional, heterotetrameric GAIT complex that binds GAIT element‐bearing mRNAs for translation‐inhibition.
      PubDate: 2017-11-20T04:25:42.057821-05:
      DOI: 10.1002/wrna.1441
  • New perspectives on telomerase RNA structure and function
    • Authors: Cherie Musgrove; Linnea I. Jansson, Michael D. Stone
      Abstract: Telomerase is an ancient ribonucleoprotein (RNP) that protects the ends of linear chromosomes from the loss of critical coding sequences through repetitive addition of short DNA sequences. These repeats comprise the telomere, which together with many accessory proteins, protect chromosomal ends from degradation and unwanted DNA repair. Telomerase is a unique reverse transcriptase (RT) that carries its own RNA to use as a template for repeat addition. Over decades of research, it has become clear that there are many diverse, crucial functions played by telomerase RNA beyond simply acting as a template. In this review, we highlight recent findings in three model systems: ciliates, yeast and vertebrates, that have shifted the way the field views the structural and mechanistic role(s) of RNA within the functional telomerase RNP complex. Viewed in this light, we hope to demonstrate that while telomerase RNA is just one example of the myriad functional RNA in the cell, insights into its structure and mechanism have wide‐ranging impacts.For further resources related to this article, please visit the WIREs website.Cross‐species conservation of telomerase RNA structure and function.
      PubDate: 2017-11-09T21:00:57.213004-05:
      DOI: 10.1002/wrna.1456
  • RNA versatility, flexibility, and thermostability for practice in RNA
           nanotechnology and biomedical applications
    • Authors: Farzin Haque; Fengmei Pi, Zhengyi Zhao, Shanqing Gu, Haibo Hu, Hang Yu, Peixuan Guo
      Abstract: In recent years, RNA has attracted widespread attention as a unique biomaterial with distinct biophysical properties for designing sophisticated architectures in the nanometer scale. RNA is much more versatile in structure and function with higher thermodynamic stability compared to its nucleic acid counterpart DNA. Larger RNA molecules can be viewed as a modular structure built from a combination of many ‘Lego’ building blocks connected via different linker sequences. By exploiting the diversity of RNA motifs and flexibility of structure, varieties of RNA architectures can be fabricated with precise control of shape, size, and stoichiometry. Many structural motifs have been discovered and characterized over the years and the crystal structures of many of these motifs are available for nanoparticle construction. For example, using the flexibility and versatility of RNA structure, RNA triangles, squares, pentagons, and hexagons can be constructed from phi29 pRNA three‐way‐junction (3WJ) building block. This review will focus on 2D RNA triangles, squares, and hexamers; 3D and 4D structures built from basic RNA building blocks; and their prospective applications in vivo as imaging or therapeutic agents via specific delivery and targeting. Methods for intracellular cloning and expression of RNA molecules and the in vivo assembly of RNA nanoparticles will also be reviewed.For further resources related to this article, please visit the WIREs website.The 3WJ motif derived from the packaging RNA of bacteriophage phi29 DNA packaging motor is highly thermodynamically stable. The 3WJ can be tuned to construct RNA triangles and squares. Through intermolecular interaction RNA hexamer can be constructed. The RNA triangular units can be further assembled into RNA 2D triangle, square, pentamer, hexamer, and arrays as well as 3D structures including tetrahedron, prism, and dendrimers. The multifunctional RNA nanoparticles have shown enormous potential as delivery vehicles for targeted cancer therapy.
      PubDate: 2017-11-03T06:21:48.700292-05:
      DOI: 10.1002/wrna.1452
  • Posttranscriptional control of airway inflammation
    • Authors: Wendy Ezegbunam; Robert Foronjy
      Abstract: Acute inflammation in the lungs is a vital protective response, efficiently and swiftly eliminating inciters of tissue injury. However, in respiratory diseases characterized by chronic inflammation, such as chronic obstructive pulmonary disease and asthma, enhanced expression of inflammatory mediators leads to tissue damage and impaired lung function. Although transcription is an essential first step in the induction of proinflammatory genes, tight regulation of inflammation requires more rapid, flexible responses. Increasing evidence shows that such responses are achieved by posttranscriptional mechanisms directly affecting mRNA stability and translation initiation. RNA‐binding proteins, microRNAs, and long noncoding RNAs interact with messenger RNA and each other to impact the stability and/or translation of mRNAs implicated in lung inflammation. Recent research has shown that these biological processes play a central role in the pathogenesis of several important pulmonary conditions. This review will highlight several posttranscriptional control mechanisms that influence lung inflammation and the known associations of derangements in these mechanisms with common respiratory diseases.For further resources related to this article, please visit the WIREs website.Posttranscriptional regulation of chemokines CCL2 and CCL7.
      PubDate: 2017-10-26T03:00:37.423558-05:
      DOI: 10.1002/wrna.1455
  • Issue information
    • PubDate: 2017-10-13T06:08:49.645294-05:
      DOI: 10.1002/wrna.1392
  • Cover Image, Volume 8, Issue 6
    • Authors: Rajat Roy; Yueyang Huang, Michael J. Seckl, Olivier E. Pardo
      Abstract: The cover image, by Rajat Roy et al., is based on Advanced Review Emerging roles of hnRNPA1 in modulating malignant transformation,
      DOI : 10.1002/wrna.1431.The cover image, by Rajat Roy et al., is based on Advanced Review Emerging roles of hnRNPA1 in modulating malignant transformation,
      DOI : 10.1002/wrna.1431.
      PubDate: 2017-10-13T06:08:48.299508-05:
  • mRNA transport in fungal top models
    • Authors: Dierk Niessing; Ralf-Peter Jansen, Thomas Pohlmann, Michael Feldbrügge
      Abstract: Eukaryotic cells rely on the precise determination of when and where proteins are synthesized. Spatiotemporal expression is supported by localization of mRNAs to specific subcellular sites and their subsequent local translation. This holds true for somatic cells as well as for oocytes and embryos. Most commonly, mRNA localization is achieved by active transport of the molecules along the actin or microtubule cytoskeleton. Key factors are molecular motors, adaptors, and RNA‐binding proteins that recognize defined sequences or structures in cargo mRNAs. A deep understanding of this process has been gained from research on fungal model systems such as Saccharomyces cerevisiae and Ustilago maydis. Recent highlights of these studies are the following: (1) synergistic binding of two RNA‐binding proteins is needed for high affinity recognition; (2) RNA sequences undergo profound structural rearrangements upon recognition; (3) mRNA transport is tightly linked to membrane trafficking; (4) mRNAs and ribosomes are transported on the cytoplasmic surface of endosomes; and (5) heteromeric protein complexes are, most likely, assembled co‐translationally during endosomal transport. Thus, the study of simple fungal model organisms provides valuable insights into fundamental mechanisms of mRNA transport boosting the understanding of similar events in higher eukaryotes.For further resources related to this article, please visit the WIREs website.Eukaryotic microorganisms like Saccharomyces cerevisiae (left) and Ustilago maydis (right) serve as role models to study actin‐ or microtubule‐dependent mRNA transport, respectively.
      PubDate: 2017-10-10T02:10:41.164026-05:
      DOI: 10.1002/wrna.1453
  • Cyclic‐di‐GMP regulation of virulence in bacterial pathogens
    • Authors: Cherisse L. Hall; Vincent T. Lee
      Abstract: Signaling pathways allow bacteria to adapt to changing environments. For pathogenic bacteria, signaling pathways allow for timely expression of virulence factors and the repression of antivirulence factors within the mammalian host. As the bacteria exit the mammalian host, signaling pathways enable the expression of factors promoting survival in the environment and/or nonmammalian hosts. One such signaling pathway uses the dinucleotide cyclic‐di‐GMP (c‐di‐GMP), and many bacterial genomes encode numerous proteins that are responsible for synthesizing and degrading c‐di‐GMP. Once made, c‐di‐GMP binds to individual protein and RNA receptors to allosterically alter the macromolecule function to drive phenotypic changes. Each bacterial genome encodes unique sets of genes for c‐di‐GMP signaling and virulence factors so the regulation by c‐di‐GMP is organism specific. Recent works have pointed to evidence that c‐di‐GMP regulates virulence in different bacterial pathogens of mammalian hosts. In this review, we discuss the criteria for determining the contribution of signaling nucleotides to pathogenesis using a well‐characterized signaling nucleotide, cyclic AMP (cAMP), in Pseudomonas aeruginosa. Using these criteria, we review the roles of c‐di‐GMP in mediating virulence and highlight common themes that exist among eight diverse pathogens that cause different diseases through different routes of infection and transmission.For further resources related to this article, please visit the WIREs website.Cyclic‐di‐GMP is a widely used signaling molecule that binds receptors to regulate phenotypes that can have an impact on the bacterial virulence in mammalian hosts.
      PubDate: 2017-10-08T22:50:28.568997-05:
      DOI: 10.1002/wrna.1454
  • RNA uridylation: a key posttranscriptional modification shaping the coding
           and noncoding transcriptome
    • Authors: Caroline De Almeida; Hélène Scheer, Hélène Zuber, Dominique Gagliardi
      Abstract: RNA uridylation is a potent and widespread posttranscriptional regulator of gene expression. RNA uridylation has been detected in a range of eukaryotes including trypanosomes, animals, plants, and fungi, but with the noticeable exception of budding yeast. Virtually all classes of eukaryotic RNAs can be uridylated and uridylation can also tag viral RNAs. The untemplated addition of a few uridines at the 3′ end of a transcript can have a decisive impact on RNA’s fate. In rare instances, uridylation is an intrinsic step in the maturation of noncoding RNAs like for the U6 spliceosomal RNA or mitochondrial guide RNAs in trypanosomes. Uridylation can also switch specific miRNA precursors from a degradative to a processing mode. This switch depends on the number of uridines added which is regulated by the cellular context. Yet, the typical consequence of uridylation on mature noncoding RNAs or their precursors is to accelerate decay. Importantly, mRNAs are also tagged by uridylation. In fact, the advent of novel high throughput sequencing protocols has recently revealed the pervasiveness of mRNA uridylation, from plants to humans. As for noncoding RNAs, the main function to date for mRNA uridylation is to promote degradation. Yet, additional roles begin to be ascribed to U‐tailing such as the control of mRNA deadenylation, translation control and possibly storage. All these new findings illustrate that we are just beginning to appreciate the diversity of roles played by RNA uridylation and its full temporal and spatial implication in regulating gene expression.For further resources related to this article, please visit the WIREs website.Uridylation is a widespread and potent posttranscriptional modification affecting the fate of coding and noncoding RNAs in eukaryotes.
      PubDate: 2017-10-05T22:00:53.037052-05:
      DOI: 10.1002/wrna.1440
  • A jack of all trades: the RNA‐binding protein vigilin
    • Authors: Matthew HK Cheng; Ralf-Peter Jansen
      Abstract: The vigilin family of proteins is evolutionarily conserved from yeast to humans and characterized by the proteins’ 14 or 15 hnRNP K homology (KH) domains, typically associated with RNA‐binding. Vigilin is the largest RNA‐binding protein (RBP) in the KH domain‐containing family and one of the largest RBP known to date. Since its identification 30 years ago, vigilin has been shown to bind over 700 mRNAs and has been associated with cancer progression and cardiovascular disease. We provide a brief historic overview of vigilin research and outline the proteins’ different functions, focusing on maintenance of genome ploidy, heterochromatin formation, RNA export, as well as regulation of translation, mRNA transport, and mRNA stability. The multitude of associated functions is reflected by the large number of identified interaction partners, ranging from tRNAs, mRNAs, ribosomes and ribosome‐associated proteins, to histone methyltransferases and DNA‐dependent protein kinases. Most of these partners bind to vigilin's carboxyterminus, and the two most C‐terminal KH domains of the protein, KH13 and KH14, represent the main mRNA‐binding interface. Since the nuclear functions of vigilins in particular are not conserved, we outline a model for the basal functions of vigilins, as well as those which were acquired during the transition from unicellular organisms to metazoa.For further resources related to this article, please visit the WIREs website.The vigilin family of proteins is involved in a variety of cellular processes via interaction with a multitude of protein partners and promiscuous binding of nucleic acids. Here we discuss 30 years of vigilin research.
      PubDate: 2017-10-04T00:45:35.711134-05:
      DOI: 10.1002/wrna.1448
  • Regulation and function of CMTR1‐dependent mRNA cap methylation
    • Authors: Francisco Inesta-Vaquera; Victoria H Cowling
      Abstract: mRNA is modified co‐transcriptionally at the 5′ end by the addition of an inverted guanosine cap structure which can be methylated at several positions. The mRNA cap recruits proteins involved in gene expression and identifies the transcript as being cellular or ‘self’ in the innate immune response. Methylation of the first transcribed nucleotide on the ribose 2′‐O position is a prevalent cap modification which has roles in splicing, translation and provides protection against the innate immune response. In this review, we discuss the regulation and function of CMTR1, the first transcribed nucleotide ribose 2′‐O methyltransferase, and the molecular interactions which mediate methylated 2′‐O ribose function.For further resources related to this article, please visit the WIREs website.CMTR1 functional domains. NLS, nuclear localization signal; G‐patch, glycine rich domain; RFM, Rossman‐fold methyltransferase domain; GT‐like, guanylyltransferase‐like domain; WW, protein interaction domain; phos, amino acid 28–66 multiple phosphorylation sites (sites with more than five references in phosphosite plus).37,38
      PubDate: 2017-10-02T21:10:35.34026-05:0
      DOI: 10.1002/wrna.1450
  • Rules and tools to predict the splicing effects of exonic and intronic
    • Authors: Kinji Ohno; Jun-ichi Takeda, Akio Masuda
      Abstract: Development of next generation sequencing technologies has enabled detection of extensive arrays of germline and somatic single nucleotide variations (SNVs) in human diseases. SNVs affecting intronic GT‐AG dinucleotides invariably compromise pre‐mRNA splicing. Most exonic SNVs introduce missense/nonsense codons, but some affect auxiliary splicing cis‐elements or generate cryptic GT‐AG dinucleotides. Similarly, most intronic SNVs are silent, but some affect canonical and auxiliary splicing cis‐elements or generate cryptic GT‐AG dinucleotides. However, prediction of the splicing effects of SNVs is challenging. The splicing effects of SNVs generating cryptic AG or disrupting canonical AG can be inferred from the AG‐scanning model. Similarly, the splicing effects of SNVs affecting the first nucleotide G of an exon can be inferred from AG‐dependence of the 3′ splice site (ss). A variety of tools have been developed for predicting the splicing effects of SNVs affecting the 5′ ss, as well as exonic and intronic splicing enhancers/silencers. In contrast, only two tools, the Human Splicing Finder and the SVM‐BP finder, are available for predicting the position of the branch point sequence. Similarly, IntSplice and Splicing based Analysis of Variants (SPANR) are the only tools to predict the splicing effects of intronic SNVs. The rules and tools introduced in this review are mostly based on observations of a limited number of genes, and no rule or tool can ensure 100% accuracy. Experimental validation is always required before any clinically relevant conclusions are drawn. Development of efficient tools to predict aberrant splicing, however, will facilitate our understanding of splicing pathomechanisms in human diseases.For further resources related to this article, please visit the WIREs website.Representative rules (red) and tools (blue) to predict the splicing effects of exonic and intronic mutations. Ex, exonic position; Int, intronic position.
      PubDate: 2017-09-26T06:00:29.867768-05:
      DOI: 10.1002/wrna.1451
  • Endonuclease Regnase‐1/Monocyte chemotactic protein‐1‐induced
           protein‐1 (MCPIP1) in controlling immune responses and beyond
    • Authors: Osamu Takeuchi
      Abstract: The activation of inflammatory cells is controlled at transcriptional and posttranscriptional levels. Posttranscriptional regulation modifies mRNA stability and translation, allowing for elaborate control of proteins required for inflammation, such as proinflammatory cytokines, prostaglandin synthases, cell surface co‐stimulatory molecules, and even transcriptional modifiers. Such regulation is important for coordinating the initiation and resolution of inflammation, and is mediated by a set of RNA‐binding proteins (RBPs), including Regnase‐1, Roquin, Tristetraprolin (TTP), and AU‐rich elements/poly(U)‐binding/degradation factor 1 (AUF1). Among these, Regnase‐1, also known as Zc3h12a and Monocyte chemotactic protein‐1‐induced protein‐1 (MCPIP1), acts as an endoribonuclease responsible for the degradation of mRNAs involved in inflammatory responses. Conversely, the RBPs Roquin and TTP trigger exonucleolytic degradation of mRNAs by recruiting the CCR4‐NOT deadenylase complex. Regnase‐1 specifically recognizes stem‐loop structures present in 3′‐untranslated regions of cytokine mRNAs, and directly degrades the mRNAs in a translation‐ and ATP‐dependent RNA helicase upframeshift 1 (UPF1)‐dependent manner that is reminiscent of nonsense‐mediated decay. Regnase‐1 regulates the activation of innate and acquired immune cells, and is critical for maintaining immune homeostasis as well as preventing over‐activation of the immune system under inflammatory conditions. Furthermore, recent studies have revealed that Regnase‐1 and its family members are involved not only in immunity but also in various biological processes. In this article, I review molecular mechanisms of Regnase‐1‐mediated mRNA decay and its physiological roles.For further resources related to this article, please visit the WIREs website.Regnase‐1/MCPIP1 is an endoribonuclease that degrades a set of mRNAs in a translation dependent manner by interacting with UPF1. Regnase‐1 recognizes mRNAs harboring a stem‐loop structure in the 3' untranslated region, and regulates various biological processes such as innate and adaptive immunity, as well as development, cancer and metabolism.
      PubDate: 2017-09-20T02:25:25.426533-05:
      DOI: 10.1002/wrna.1449
  • Advances and challenges in the detection of transcriptome-wide
           protein–RNA interactions
    • Authors: Emily C. Wheeler; Eric L. Van Nostrand, Gene W. Yeo
      Abstract: RNA binding proteins (RBPs) play key roles in determining cellular behavior by manipulating the processing of target RNAs. Robust methods are required to detect the numerous binding sites of RBPs across the transcriptome. RNA-immunoprecipitation followed by sequencing (RIP-seq) and crosslinking followed by immunoprecipitation and sequencing (CLIP-seq) are state-of-the-art methods used to identify the RNA targets and specific binding sites of RBPs. Historically, CLIP methods have been confounded with challenges such as the requirement for tens of millions of cells per experiment, low RNA yields resulting in libraries that contain a high number of polymerase chain reaction duplicated reads, and technical inconveniences such as radioactive labeling of RNAs. However, recent improvements in the recovery of bound RNAs and the efficiency of converting isolated RNAs into a library for sequencing have enhanced our ability to perform the experiment at scale, from less starting material than has previously been possible, and resulting in high quality datasets for the confident identification of protein binding sites. These, along with additional improvements to protein capture, removal of nonspecific signals, and methods to isolate noncanonical RBP targets have revolutionized the study of RNA processing regulation, and reveal a promising future for mapping the human protein-RNA regulatory network.For further resources related to this article, please visit the WIREs website.Methods to capture protein-RNA interactions. Different techniques are required to capture single-stranded (green), double-stranded (blue), and indirect (yellow) RNA interactions. Crosses (X) in red mark RNA sites that are crosslinked to the RNA binding protein. (right) UV treatment at 254 nm preferentially captures binding in single-stranded regions. (bottom right) 0.1% formaldehyde treatment captures all protein-protein and protein-RNA interactions. (bottom left) RNA immunoprecipitation (RIP) uses a native pulldown (no crosslinking) to capture binding events with antibody selection. Optimized RNA digestion conditions can reveal specific binding sites with RIP. (left) Photoactivatable ribonucleoside analog treatment (PAR) increases UV crosslinking efficiency at 365 nm. (top left) Methylene blue intercalates between the bases of double-stranded RNA to allow crosslinking in double-stranded regions in the presence of visible light. (top right) Protein-RNA interaction sites are marked by exogenous RNA modifications. This requires creating a fusion protein to modify RNA near binding sites with biotinylation (BioTag-BirA) or A-to-I RNA editing (ADAR).
      PubDate: 2017-08-29T21:35:36.80863-05:0
      DOI: 10.1002/wrna.1436
  • Chromatin-associated noncoding RNAs in development and inheritance
    • Authors: Sreemukta Acharya; Mark Hartmann, Sylvia Erhardt
      Abstract: Noncoding RNAs (ncRNAs) have emerged as crucial players in chromatin regulation. Their diversity allows them to partake in the regulation of numerous cellular processes across species. During development, long and short ncRNAs act in conjunction with each other where long ncRNAs (lncRNAs) are best understood in establishing appropriate gene expression patterns, while short ncRNAs (sRNAs) are known to establish constitutive heterochromatin and suppress mobile elements. Additionally, increasing evidence demonstrates roles of sRNAs in several typically lncRNA-mediated processes such as dosage compensation, indicating a complex regulatory network of noncoding RNAs. Together, various ncRNAs establish many mitotically heritable epigenetic marks during development. Additionally, they participate in mechanisms that regulate maintenance of these epigenetic marks during the lifespan of the organism. Interestingly, some epigenetic traits are transmitted to the next generation(s) via paramutations or transgenerational inheritance mediated by sRNAs. In this review, we give an overview of the various functions and regulations of ncRNAs and the mechanisms they employ in the establishment and maintenance of epigenetic marks and multi-generational transmission of epigenetic traits.For further resources related to this article, please visit the WIREs website.Different types of chromatin associated non-coding RNAs are crucial for many organismal and cellular processes.
      PubDate: 2017-08-25T01:26:07.291385-05:
      DOI: 10.1002/wrna.1435
  • Urinary microRNAs for prostate cancer diagnosis, prognosis, and treatment
           response: are we there yet'
    • Authors: Ovidiu Balacescu; Bogdan Petrut, Oana Tudoran, Dragos Feflea, Loredana Balacescu, Andrei Anghel, Ioan O. Sirbu, Edward Seclaman, Catalin Marian
      Abstract: Prostate cancer (PCa) remains one of the leading causes of cancer-related deaths in men. Despite the tremendous progress in research over the years, a suitable minimally invasive PCa biomarker is yet to be discovered. The recent advances regarding the roles of microRNAs as biomarkers has allowed for their study in PCa as well, especially as blood-based markers. However, there are several studies that used urine as biological sample to evaluate microRNAs as biomarkers for PCa diagnosis, prognosis, and treatment response, which were reviewed herein. A high degree of inconsistency among reports has been observed, which could be due to several analytical aspects, starting with different urinary fractions used for analysis and continuing with the employment of various analytical platforms and methods of statistical analysis. However, a few microRNAs were found to be dysregulated in the urine of PCa patients, which alone or together with serum prostate-specific antigen seem to improve diagnostic power even in the gray zone of PCa. These results warrant further confirmation by larger prospective studies, preferably using a standardized protocol for analysis.For further resources related to this article, please visit the WIREs website.Urinary miRNAs and their role in diagnosis, prognosis, and treatment response of prostate cancer.
      PubDate: 2017-08-16T02:25:30.803451-05:
      DOI: 10.1002/wrna.1438
  • Organization of the Flavivirus RNA replicase complex
    • Authors: Carolin Brand; Martin Bisaillon, Brian J. Geiss
      Abstract: Flaviviruses, such as dengue, Japanese encephalitis, West Nile, yellow fever, and Zika viruses, are serious human pathogens that cause significant morbidity and mortality globally each year. Flaviviruses are single-stranded, positive-sense RNA viruses, and encode two multidomain proteins, NS3 and NS5, that possess all enzymatic activities required for genome replication and capping. NS3 and NS5 interact within virus-induced replication compartments to form the RNA genome replicase complex. Although the individual enzymatic activities of both proteins have been extensively studied and are well characterized, there are still gaps in our understanding of how they interact to efficiently coordinate their respective activities during positive-strand RNA synthesis and capping. Here, we discuss what is known about the structures and functions of the NS3 and NS5 proteins and propose a preliminary NS3:NS5:RNA interaction model based on a large body of literature about how the viral enzymes function, physical restraints between NS3 and NS5, as well as critical steps in the replication process.For further resources related to this article, please visit the WIREs website.Association of Flavivirus NS3 helicase (blue) and NS5 polymerase (red) is essential for viral RNA genome replication.
      PubDate: 2017-08-16T02:22:20.535057-05:
      DOI: 10.1002/wrna.1437
  • RNA-mediated signal perception in pathogenic bacteria
    • Authors: Dmitriy Ignatov; Jörgen Johansson
      Abstract: Bacterial pathogens encounter several different environments during an infection, many of them possibly being detrimental. In order to sense its surroundings and adjust the gene expression accordingly, different regulatory schemes are undertaken. With these, the bacterium appropriately can differentiate between various environmental cues to express the correct virulence factor at the appropriate time and place. An attractive regulator device is RNA, which has an outstanding ability to alter its structure in response to external stimuli, such as metabolite concentration or alterations in temperature, to control its downstream gene expression. This review will describe the function of riboswitches and thermometers, with a particular emphasis on regulatory RNAs being important for bacterial pathogenicity.For further resources related to this article, please visit the WIREs website.RNA sensing in pathogenic bacteria.
      PubDate: 2017-08-09T05:35:37.727103-05:
      DOI: 10.1002/wrna.1429
  • Emerging roles of hnRNPA1 in modulating malignant transformation
    • Authors: Rajat Roy; Yueyang Huang, Michael J. Seckl, Olivier E. Pardo
      Abstract: Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins associated with complex and diverse biological processes such as processing of heterogeneous nuclear RNAs (hnRNAs) into mature mRNAs, RNA splicing, transactivation of gene expression, and modulation of protein translation. hnRNPA1 is the most abundant and ubiquitously expressed member of this protein family and has been shown to be involved in multiple molecular events driving malignant transformation. In addition to selective mRNA splicing events promoting expression of specific protein variants, hnRNPA1 regulates the gene expression and translation of several key players associated with tumorigenesis and cancer progression. Here, we will summarize our current knowledge of the involvement of hnRNPA1 in cancer, including its roles in regulating cell proliferation, invasiveness, metabolism, adaptation to stress and immortalization.For further resources related to this article, please visit the WIREs website.hnRNPA1 is involved in multiple biological processes within the cell nucleus and cytoplasm. Counter-clockwise: hnRNPA1 regulates mRNA stability, the transcription of G-quadruplex containing genes, the nuclear export and translational de-repression of IRES-containing mRNAs, mRNA splicing and telomere length maintenance.
      PubDate: 2017-08-08T23:30:52.790247-05:
      DOI: 10.1002/wrna.1431
  • The La and related RNA-binding proteins (LARPs): structures, functions,
           and evolving perspectives
    • Authors: Richard J. Maraia; Sandy Mattijssen, Isabel Cruz-Gallardo, Maria R. Conte
      Abstract: La was first identified as a polypeptide component of ribonucleic protein complexes targeted by antibodies in autoimmune patients and is now known to be a eukaryote cell-ubiquitous protein. Structure and function studies have shown that La binds to a common terminal motif, UUU-3′-OH, of nascent RNA polymerase III (RNAP III) transcripts and protects them from exonucleolytic decay. For precursor-tRNAs, the most diverse and abundant of these transcripts, La also functions as an RNA chaperone that helps to prevent their misfolding. Related to this, we review evidence that suggests that La and its link to RNAP III were significant in the great expansions of the tRNAomes that occurred in eukaryotes. Four families of La-related proteins (LARPs) emerged during eukaryotic evolution with specialized functions. We provide an overview of the high-resolution structural biology of La and LARPs. LARP7 family members most closely resemble La but function with a single RNAP III nuclear transcript, 7SK, or telomerase RNA. A cytoplasmic isoform of La protein as well as LARPs 6, 4, and 1 function in mRNA metabolism and translation in distinct but similar ways, sometimes with the poly(A)-binding protein, and in some cases by direct binding to poly(A)-RNA. New structures of LARP domains, some complexed with RNA, provide novel insights into the functional versatility of these proteins. We also consider LARPs in relation to ancestral La protein and potential retention of links to specific RNA-related pathways. One such link may be tRNA surveillance and codon usage by LARP-associated mRNAs.For further resources related to this article, please visit the WIREs website.La and La-related proteins (LARPs) share a La module RNA-binding platform and serve a variety of fundamental functions. La and its homologs LARP7, p65, and p43 associate with RNA polymerase-III-derived small RNAs in the nucleus, whereas LARPs 1, 4, and 6 function with cytoplasmic mRNAs.
      PubDate: 2017-08-07T01:01:35.261202-05:
      DOI: 10.1002/wrna.1430
  • Ancient and modern: hints of a core post-transcriptional network driving
           chemotherapy resistance in ovarian cancer
    • Authors: Sarah Blagden; Mai Abdel Mouti, James Chettle
      Abstract: RNA-binding proteins (RBPs) and noncoding (nc)RNAs (such as microRNAs, long ncRNAs, and others) cooperate within a post-transcriptional network to regulate the expression of genes required for many aspects of cancer behavior including its sensitivity to chemotherapy. Here, using an RBP-centric approach, we explore the current knowledge surrounding contributers to post-transcriptional gene regulation (PTGR) in ovarian cancer and identify commonalities that hint at the existence of an evolutionarily conserved core PTGR network. This network regulates survival and chemotherapy resistance in the contemporary context of the cancer cell. There is emerging evidence that cancers become dependent on PTGR factors for their survival. Further understanding of this network may identify innovative therapeutic targets as well as yield crucial insights into the hard-wiring of many malignancies, including ovarian cancer.For further resources related to this article, please visit the WIREs website.(a)–(c) RNA-binding proteins influence epithelial ovarian cancer (EOC) progression through complex networks with mRNAs, noncoding RNAs, and other proteins. (a) RNA-binding motif protein 3 (RBM3) regulates platinum sensitivity and patient survival through regulation of mRNAs involved in apoptosis and the stress response. (b) HuR exerts an oncogenic effect through stabilization and therefore increased translation of a range of mRNAs. (c) RNA-binding proteins, such as YB1, LARP1, and IMP1 may converge on multiple subsets of mRNAs and signaling pathways as part of a network that drives progression of EOC and/or resistance to chemotherapy.
      PubDate: 2017-08-01T01:40:30.190652-05:
      DOI: 10.1002/wrna.1432
  • Single cell transcriptomics of noncoding RNAs and their cell-specificity
    • Authors: Katerina A.B. Gawronski; Junhyong Kim
      Abstract: Recent developments of single cell transcriptome profiling methods have led to the realization that many seemingly homogeneous cells have surprising levels of expression variability. The biological implications of the high degree of variability is unclear but one possibility is that many genes are restricted in expression to small lineages of cells, suggesting the existence of many more cell types than previously estimated. Noncoding RNA (ncRNA) are thought to be key parts of gene regulatory processes and their single cell expression patterns may help to dissect the biological function of single cell variability. Technology for measuring ncRNA in single cell is still in development and most of the current single cell datasets have reliable measurements for only long noncoding RNA (lncRNA). Most works report that lncRNAs show lineage-specific restricted expression patterns, which suggest that they might determine, at least in part, lineage fates and cell subtypes. However, evidence is still inconclusive as to whether lncRNAs and other ncRNAs are more lineage-specific than protein-coding genes. Nevertheless, measurement of ncRNAs in single cells will be important for studies of cell types and single cell function.For further resources related to this article, please visit the WIREs website.Single cell transcriptome analysis reveals cell-to-cell variability in noncoding RNA expression
      PubDate: 2017-08-01T01:25:26.197987-05:
      DOI: 10.1002/wrna.1433
  • An emerging model organism Caenorhabditis elegans for alternative pre-mRNA
           processing in vivo
    • Authors: Shotaro Wani; Hidehito Kuroyanagi
      Abstract: A nematode Caenorhabditis elegans is an intron-rich organism and up to 25% of its pre-mRNAs are estimated to be alternatively processed. Its compact genomic organization enables construction of fluorescence splicing reporters with intact genomic sequences and visualization of alternative processing patterns of interest in the transparent living animals with single-cell resolution. Genetic analysis with the reporter worms facilitated identification of trans-acting factors and cis-acting elements, which are highly conserved in mammals. Analysis of unspliced and partially spliced pre-mRNAs in vivo raised models for alternative splicing regulation relying on specific order of intron excision. RNA-seq analysis of splicing factor mutants and CLIP-seq analysis of the factors allow global search for target genes in the whole animal. An mRNA surveillance system is not essential for its viability or fertility, allowing analysis of unproductively spliced noncoding mRNAs. These features offer C. elegans as an ideal model organism for elucidating alternative pre-mRNA processing mechanisms in vivo. Examples of isoform-specific functions of alternatively processed genes are summarized.For further resources related to this article, please visit the WIREs website.Recent progress in fluorescence reporter system and deep sequencing technologies turn C. elegans an excellent multicellular model organism for elucidating pre-mRNA processing regulation in vivo
      PubDate: 2017-07-13T04:50:26.379606-05:
      DOI: 10.1002/wrna.1428
  • Chimeric RNAs in cancer and normal physiology
    • Authors: Katarzyna Chwalenia; Loryn Facemire, Hui Li
      Abstract: Traditionally, chimeric RNAs were considered to be exclusive to cancer cells. When occasionally observed in normal samples, they were usually considered to be transcriptional ‘noises,’ or artifacts due to template switching during the reverse transcription and/or Polymerase chain reaction (PCR) steps of experimentation. However, with the advances being made in next generation sequencing technologies and software tools, as well as the accumulation of new experimental evidences, increasing numbers of chimeric transcripts are being identified in noncancerous tissues and cells. Recent studies have also demonstrated functional relevance, for at least a subset of chimeric RNAs in normal physiology. The advances have resulted in an influx of knowledge; this knowledge indicates that chimeric RNAs are a component of basic biology, and thus challenging traditional dogma. In addition to chromosomal rearrangement, chimeric RNAs can also be formed via different molecular mechanisms including cis-splicing of adjacent genes (cis-SAGe) and trans-splicing, as well as others. Little is known about the details of these noncanonical splicing processes. However, research in this new field promises to not only advance our basic understanding of the human genome and gene regulation, but also lead to improvements in clinical practice, especially in the areas of cancer diagnostics and treatment.For further resources related to this article, please visit the WIREs website.Chimeric RNAs can be generated not only by chromosomal rearrangements at DNA level, but also by intergenic splicing at RNA level. Nowadays, they are often identified through RNA-Seq. Chimeric RNAs are demonstrated not only to be the elusive features of cancer cells but also present in normal physiology. They can have diverse functions. This review summarized the generating mechanisms of chimeric RNAs, discussed different models, described approaches to identify chimeric RNAs, highlighted their relevance in cancer and normal cells, and offered our insights on the topic and directions for the future research.
      PubDate: 2017-06-07T02:30:30.698387-05:
      DOI: 10.1002/wrna.1427
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