Journal Cover Wiley Interdisciplinary Reviews : RNA
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   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Online) 1757-7012
   Published by John Wiley and Sons Homepage  [1592 journals]
  • Noncoding RNAs in Alzheimer's disease
    • Authors: M. Laura Idda; Rachel Munk, Kotb Abdelmohsen, Myriam Gorospe
      Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia among the elderly worldwide. Despite intense efforts to develop drugs for preventing and treating AD, no effective therapies are available as yet, posing a growing burden at the personal, medical, and socioeconomic levels. AD is characterized by the production and aggregation of amyloid β (Aβ) peptides derived from amyloid precursor protein (APP), the presence of hyperphosphorylated microtubule-associated protein Tau (MAPT), and chronic inflammation leading to neuronal loss. Aβ accumulation and hyperphosphorylated Tau are responsible for the main histopathological features of AD, Aβ plaques, and neurofibrillary tangles (NFTs), respectively. However, the full spectrum of molecular factors that contribute to AD pathogenesis is not known. Noncoding (nc)RNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), regulate gene expression at the transcriptional and posttranscriptional levels in various diseases, serving as biomarkers and potential therapeutic targets. There is rising recognition that ncRNAs have been implicated in both the onset and pathogenesis of AD. Here, we review the ncRNAs implicated posttranscriptionally in the main AD pathways and discuss the growing interest in targeting regulatory ncRNAs therapeutically to combat AD pathology.This article is categorized under:RNA in Disease and Development > RNA in DiseaseSchematic of the three main domains of AD pathogenesis. Top, APP is cleaved by α, β, and γ secretases; the generation and aggregation of amyloidogenic Aβ peptides outside of the cell leads to the formation of amyloid plaques. Bottom, the hyperphosphorylation of Tau protein results in formation of intracellular neurofibrillary tangles. Right, amyloid plaques and neurofibrillary tangles create a toxic environment characterized by neuroinflammation and neurodegeneration. Key, top right
      PubDate: 2018-01-12T01:20:35.215134-05:
      DOI: 10.1002/wrna.1463
       
  • Cold-inducible RNA binding protein in cancer and inflammation
    • Authors: Daniel A. Lujan; Joey L. Ochoa, Rebecca S. Hartley
      Abstract: RNA binding proteins (RBPs) play key roles in RNA dynamics, including subcellular localization, translational efficiency and metabolism. Cold-inducible RNA binding protein (CIRP) is a stress-induced protein that was initially described as a DNA damage-induced transcript (A18 hnRNP), as well as a cold-shock domain containing cold-stress response protein (CIRBP) that alters the translational efficiency of its target messenger RNAs (mRNAs). This review summarizes recent work on the roles of CIRP in the context of inflammation and cancer. The function of CIRP in cancer appeared to be solely driven though its functions as an RBP that targeted cancer-associated mRNAs, but it is increasingly clear that CIRP also modulates inflammation. Several recent studies highlight roles for CIRP in immune responses, ranging from sepsis to wound healing and tumor-promoting inflammation. While modulating inflammation is an established role for RBPs that target cytokine mRNAs, CIRP appears to modulate inflammation by several different mechanisms. CIRP has been found in serum, where it binds the TLR4-MD2 complex, acting as a Damage-associated molecular pattern (DAMP). CIRP activates the NF-κB pathway, increasing phosphorylation of Iκκ and IκBα, and stabilizes mRNAs encoding pro-inflammatory cytokines. While CIRP promotes higher levels of pro-inflammatory cytokines in certain cancers, it also decreases inflammation to accelerate wound healing. This dichotomy suggests that the influence of CIRP on inflammation is context dependent and highlights the importance of detailing the mechanisms by which CIRP modulates inflammation.This article is categorized under:RNA in Disease and Development > RNA in DiseaseRNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional ImplicationsSummary of CIRP Roles in Inflammation and Cancer. CIRP shuttles from the nucleus to the cytoplasm to bind the 3' UTRs of target mRNA to increase their translation. It is possible that CIRP can bind tumor promoting cytokines in certain contexts. CIRP in found extracellularly in patients with sepsis (likely through lysosomal secretion) where it binds the TLR-4 MD2 complex, functioning as a DAMP and stimulating cytokine release from APCs. Also, CIRP increases I phosphorylation through an unknown mechanism. Arrows and boxes in black represent known roles from literature and red dashed arrows and boxes represent possible mechanisms or connections.
      PubDate: 2018-01-11T00:55:54.253942-05:
      DOI: 10.1002/wrna.1462
       
  • Molecular and genetic interactions of the RNA degradation machineries in
           Firmicute bacteria
    • Authors: Peter Redder
      Abstract: Correct balance between bacterial RNA degradation and synthesis is essential for controlling expression level of all RNAs. The RNA polymerase, which performs the RNA synthesis, is highly conserved across the bacterial domain. However, this is surprisingly not the case for the RNA degradation machinery, which is composed of different subunits and performs different enzymatic reactions, depending on the organism. In Escherichia coli, the RNA decay is performed by the degradosome complex, which forms around the membrane‐associated endoribonuclease RNase E, and is stable enough to be purified without falling apart. In contrast, many Firmicutes, for example, Bacillus subtilis, Staphylococcus aureus, and Streptococcus pneumoniae, do not encode an RNase E homolog, but instead have the endoribonuclease RNase Y and the exo‐ and endo‐ribonuclease RNase J complex. A wide range of experiments have been performed, mainly with B. subtilis and S. aureus, to determine which interactions exist between the various RNA decay enzymes in the Firmicutes, with the goal of understanding how RNA degradation (and thus gene expression homeostasis and regulation) is organized in these organisms. The in vivo and in vitro data is diverse, and does not always concur. This overview gathers the data on interactions between Firmicute RNA degradation factors, to highlight the similarities and differences between experimental data from different experiments and from different organisms.This article is categorized under:RNA Turnover and Surveillance > Turnover/Surveillance MechanismsRNA Turnover and Surveillance > Regulation of RNA StabilitySchematic overview of the main interactions within the network of the RNA degradation machinery.
      PubDate: 2018-01-05T00:47:24.056568-05:
      DOI: 10.1002/wrna.1460
       
  • Emerging roles of RNA‐binding proteins in diabetes and their therapeutic
           potential in diabetic complications
    • Authors: Curtis A. Nutter; Muge N. Kuyumcu-Martinez
      Abstract: Diabetes is a debilitating health care problem affecting 422 million people around the world. Diabetic patients suffer from multisystemic complications that can cause mortality and morbidity. Recent advancements in high‐throughput next‐generation RNA‐sequencing and computational algorithms led to the discovery of aberrant posttranscriptional gene regulatory programs in diabetes. However, very little is known about how these regulatory programs are mis‐regulated in diabetes. RNA‐binding proteins (RBPs) are important regulators of posttranscriptional RNA networks, which are also dysregulated in diabetes. Human genetic studies provide new evidence that polymorphisms and mutations in RBPs are linked to diabetes. Therefore, we will discuss the emerging roles of RBPs in abnormal posttranscriptional gene expression in diabetes. Questions that will be addressed are: Which posttranscriptional mechanisms are disrupted in diabetes' Which RBPs are responsible for such changes under diabetic conditions' How are RBPs altered in diabetes' How does dysregulation of RBPs contribute to diabetes' Can we target RBPs using RNA‐based methods to restore gene expression profiles in diabetic patients' Studying the evolving roles of RBPs in diabetes is critical not only for a comprehensive understanding of diabetes pathogenesis but also to design RNA‐based therapeutic approaches for diabetic complications.This article is categorized under:RNA in Disease and Development > RNA in DiseaseRNA Processing > Splicing Regulation/Alternative SplicingTranslation > Translation RegulationRole of RNA‐binding proteins in development of diabetes and diabetic complications.
      PubDate: 2017-12-27T04:03:35.256266-05:
      DOI: 10.1002/wrna.1459
       
  • Cover Image, Volume 9, Issue 1
    • Authors: Dierk Niessing; Ralf-Peter Jansen, Thomas Pohlmann, Michael Feldbrügge
      Abstract: The cover image, by Dierk Niessing et al., is based on the Focus Article mRNA transport in fungal top models,
      DOI : 10.1002/wrna.1453. Image Credit: CEPLAS ‐ Cluster of Excellence on Plant SciencesThe cover image, by Dierk Niessing et al., is based on the Focus Article mRNA transport in fungal top models,
      DOI : 10.1002/wrna.1453. Image Credit: CEPLAS ‐ Cluster of Excellence on Plant Sciences
      PubDate: 2017-12-21T03:23:16.462703-05:
       
  • Issue information
    • PubDate: 2017-12-21T03:23:13.157261-05:
      DOI: 10.1002/wrna.1442
       
  • 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
       
  • 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
       
  • Rules and tools to predict the splicing effects of exonic and intronic
           mutations
    • 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
       
  • 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
       
  • Mutually exclusive alternative splicing of pre‐mRNAs
    • Abstract: Pre‐mRNA alternative splicing is an important mechanism used to expand protein diversity in higher eukaryotes, and mutually exclusive splicing is a specific type of alternative splicing in which only one of the exons in a cluster is included in functional transcripts. The most extraordinary example of this is the Drosophila melanogaster Down’s syndrome cell adhesion molecule gene (Dscam), which potentially encodes 38,016 different isoforms through mutually exclusive splicing. Mutually exclusive splicing is a unique and challenging model that can be used to elucidate the evolution, regulatory mechanism, and function of alternative splicing. The use of new approaches has not only greatly expanded the mutually exclusive exome, but has also enabled the systematic analyses of single‐cell alternative splicing during development. Furthermore, the identification of long‐range RNA secondary structures provides a mechanistic framework for the regulation of mutually exclusive splicing (i.e., Dscam splicing). This article reviews recent insights into the identification, underlying mechanism, and roles of mutually exclusive splicing.This article is categorized under:RNA Processing > Splicing Regulation/Alternative SplicingRNA Structure and Dynamics > Influence of RNA Structure in Biological SystemsRecent progress range from the genome‐wide identification of mutually exclusive splicing events to the elucidation of underlying mechanism and function.
       
  • Circadian processes in the RNA life cycle
    • Abstract: The circadian clock drives daily rhythms of multiple physiological processes, allowing organisms to anticipate and adjust to periodic changes in environmental conditions. These physiological rhythms are associated with robust oscillations in the expression of at least 30% of expressed genes. While the ability for the endogenous timekeeping system to generate a 24‐hr cycle is a cell‐autonomous mechanism based on negative autoregulatory feedback loops of transcription and translation involving core‐clock genes and their protein products, it is now increasingly evident that additional mechanisms also govern the circadian oscillations of clock‐controlled genes. Such mechanisms can take place post‐transcriptionally during the course of the RNA life cycle. It has been shown that many steps during RNA processing are regulated in a circadian manner, thus contributing to circadian gene expression. These steps include mRNA capping, alternative splicing, changes in splicing efficiency, and changes in RNA stability controlled by the tail length of polyadenylation or the use of alternative polyadenylation sites. RNA transport can also follow a circadian pattern, with a circadian nuclear retention driven by rhythmic expression within the nucleus of particular bodies (the paraspeckles) and circadian export to the cytoplasm driven by rhythmic proteins acting like cargo. Finally, RNA degradation may also follow a circadian pattern through the rhythmic involvement of miRNAs. In this review, we summarize the current knowledge of the post‐transcriptional circadian mechanisms known to play a prominent role in shaping circadian gene expression in mammals.This article is categorized under:RNA Processing > Splicing Regulation/Alternative SplicingRNA Processing > RNA Editing and ModificationRNA Export and Localization > Nuclear Export/ImportAll steps of the RNA life cycle are under the circadian clock control.
       
  • Therapeutic applications of group I intron‐based
           trans‐splicing ribozymes
    • Abstract: Since the breakthrough discovery of catalytic RNAs (ribozymes) in the early 1980s, valuable ribozyme‐based gene therapies have been developed for incurable diseases ranging from genetic disorders to viral infections and cancers. Ribozymes can be engineered and used to downregulate or repair pathogenic genes via RNA cleavage mediated by trans‐cleaving ribozymes or repair and reprograming mediated by trans‐splicing ribozymes, respectively. Uniquely, trans‐splicing ribozymes can edit target RNAs via simultaneous destruction and repair (and/or reprograming) to yield the desired therapeutic RNAs, thus selectively inducing therapeutic gene activity in cells expressing the target RNAs. In contrast to traditional gene therapy approaches, such as simple addition of therapeutic transgenes or inhibition of disease‐causing genes, the selective repair and/or reprograming abilities of trans‐splicing ribozymes in target RNA‐expressing cells facilitates the maintenance of endogenous spatial and temporal gene regulation and reduction of disease‐associated transcript expression. In molecular imaging technologies, trans‐splicing ribozymes can be used to reprogram specific RNAs in living cells and organisms by the 3′‐tagging of reporter RNAs. The past two decades have seen progressive improvements in trans‐splicing ribozymes and the successful application of these elements in gene therapy and molecular imaging approaches for various pathogenic conditions, such as genetic, infectious, and malignant disease. This review provides an overview of the current status of trans‐splicing ribozyme therapeutics, focusing on Tetrahymena group I intron‐based ribozymes, and their future prospects.This article is categorized under:RNA in Disease and Development > RNA in DiseaseGroup I intron‐based trans‐splicing ribozyme specifically recognizes disease‐specific or associated RNA, removes the sequence downstream of the target site, and replaces it with a 3′‐exon encoding a therapeutic/reporter RNA sequence, inducing therapeutic/reporter activity selectively in the target RNA‐expressing cells.
       
  • Trans‐acting translational regulatory RNA binding proteins
    • Abstract: The canonical molecular machinery required for global mRNA translation and its control has been well defined, with distinct sets of proteins involved in the processes of translation initiation, elongation and termination. Additionally, noncanonical, trans‐acting regulatory RNA‐binding proteins (RBPs) are necessary to provide mRNA‐specific translation, and these interact with 5′ and 3′ untranslated regions and coding regions of mRNA to regulate ribosome recruitment and transit. Recently it has also been demonstrated that trans‐acting ribosomal proteins direct the translation of specific mRNAs. Importantly, it has been shown that subsets of RBPs often work in concert, forming distinct regulatory complexes upon different cellular perturbation, creating an RBP combinatorial code, which through the translation of specific subsets of mRNAs, dictate cell fate. With the development of new methodologies, a plethora of novel RNA binding proteins have recently been identified, although the function of many of these proteins within mRNA translation is unknown. In this review we will discuss these methodologies and their shortcomings when applied to the study of translation, which need to be addressed to enable a better understanding of trans‐acting translational regulatory proteins. Moreover, we discuss the protein domains that are responsible for RNA binding as well as the RNA motifs to which they bind, and the role of trans‐acting ribosomal proteins in directing the translation of specific mRNAs.This article is categorized under:RNA Interactions with Proteins and Other Molecules > RNA–Protein ComplexesTranslation > Translation RegulationTranslation > Translation MechanismsTrans‐acting RNA binding proteins (RBPs) regulate mRNA translation by interacting with sequence elements in the 5′ and 3′ untranslated regions. These RBPs can control recruitment of the mRNAs to the ribosome and regulate the rate of protein synthesis or alternatively, repress mRNA translation through regulating mRNA instability/degradation.
       
  • Natural antisense transcripts in diseases: From modes of action to
           targeted therapies
    • Abstract: Antisense transcription is a widespread phenomenon in mammalian genomes, leading to production of RNAs molecules referred to as natural antisense transcripts (NATs). NATs apply diverse transcriptional and post‐transcriptional regulatory mechanisms to carry out a wide variety of biological roles that are important for the normal functioning of living cells, but their dysfunctions can be associated with human diseases. In this review, we attempt to provide a molecular basis for the involvement of NATs in the etiology of human disorders such as cancers and neurodegenerative and cardiovascular diseases. We also discuss the pros and cons of oligonucleotide‐based therapies targeted against NATs, and we comment on state‐of‐the‐art progress in this promising area of clinical research.This article is categorized under:RNA in Disease and Development > RNA in DiseaseRegulatory RNAs/RNAi/Riboswitches > Regulatory RNAsRNA Interactions with Proteins and Other Molecules > Small Molecule–RNA InteractionsNatural antisense transcripts (NATs) are potent regulators of gene expression and as such they are implicated in aethiology of a number of human diseases.
       
 
 
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