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Journal Cover   Wiley Interdisciplinary Reviews : RNA
  [SJR: 5.014]   [H-I: 21]   [3 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Online) 1757-7012
   Published by John Wiley and Sons Homepage  [1597 journals]
  • To edit or not to edit: regulation of ADAR editing specificity and
    • Authors: Sarah N. Deffit; Heather A. Hundley
      Abstract: Hundreds to millions of adenosine (A)‐to‐inosine (I) modifications are present in eukaryotic transcriptomes and play an essential role in the creation of proteomic and phenotypic diversity. As adenosine and inosine have different base‐pairing properties, the functional consequences of these modifications or ‘edits’ include altering coding potential, splicing, and miRNA‐mediated gene silencing of transcripts. However, rather than serving as a static control of gene expression, A‐to‐I editing provides a means to dynamically rewire the genetic code during development and in a cell‐type specific manner. Interestingly, during normal development, in specific cells, and in both neuropathological diseases and cancers, the extent of RNA editing does not directly correlate with levels of the substrate mRNA or the adenosine deaminase that act on RNA (ADAR) editing enzymes, implying that cellular factors are required for spatiotemporal regulation of A‐to‐I editing. The factors that affect the specificity and extent of ADAR activity have been thoroughly dissected in vitro. Yet, we still lack a complete understanding of how specific ADAR family members can selectively deaminate certain adenosines while others cannot. Additionally, in the cellular environment, ADAR specificity and editing efficiency is likely to be influenced by cellular factors, which is currently an area of intense investigation. Data from many groups have suggested two main mechanisms for controlling A‐to‐I editing in the cell: (1) regulating ADAR accessibility to target RNAs and (2) protein–protein interactions that directly alter ADAR enzymatic activity. Recent studies suggest cis‐ and trans‐acting RNA elements, heterodimerization and RNA‐binding proteins play important roles in regulating RNA editing levels in vivo.
      PubDate: 2015-11-26T22:19:20.676396-05:
      DOI: 10.1002/wrna.1319
  • Rrp6: Integrated roles in nuclear RNA metabolism and transcription
    • Authors: Melanie J. Fox; Amber L. Mosley
      Abstract: The yeast RNA exosome is a eukaryotic ribonuclease complex essential for RNA processing, surveillance, and turnover. It is comprised of a barrel‐shaped core and cap as well as a 3′–5′ ribonuclease known as Dis3 that contains both endo‐ and exonuclease domains. A second exonuclease, Rrp6, is added in the nucleus. Dis3 and Rrp6 have both shared and distinct roles in RNA metabolism, and this review will focus primarily on Rrp6 and the roles of the RNA exosome in the nucleus. The functions of the nuclear exosome are modulated by cofactors and interacting partners specific to each type of substrate. Generally, the cofactor TRAMP (Trf4/5–Air2/1–Mtr4 polyadenylation) complex helps unwind unstable RNAs, RNAs requiring processing such as rRNAs, tRNAs, or snRNAs or improperly processed RNAs and direct it toward the exosome. In yeast, Rrp6 interacts with Nrd1, the cap‐binding complex, and RNA polymerase II to aid in nascent RNA processing, termination, and polyA tail length regulation. Recent studies have shown that proper termination and processing of short, noncoding RNAs by Rrp6 is particularly important for transcription regulation across the genome and has important implications for regulation of diverse processes at the cellular level. Loss of proper Rrp6 and exosome activity may contribute to various pathologies such as autoimmune disease, neurological disorders, and cancer. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-11-26T20:51:44.497234-05:
      DOI: 10.1002/wrna.1317
  • Cytoplasmic polyadenylation in mammalian oocyte maturation
    • Authors: Juan M. Reyes; Pablo J. Ross
      Abstract: Oocyte developmental competence is the ability of the mature oocyte to be fertilized and subsequently drive early embryo development. Developmental competence is acquired by completion of oocyte maturation, a process that includes nuclear (meiotic) and cytoplasmic (molecular) changes. Given that maturing oocytes are transcriptionally quiescent (as are early embryos), they depend on post‐transcriptional regulation of stored transcripts for protein synthesis, which is largely mediated by translational repression and deadenylation of transcripts within the cytoplasm, followed by recruitment of specific transcripts in a spatiotemporal manner for translation during oocyte maturation and early development. Motifs within the 3′ untranslated region (UTR) of messenger RNA (mRNA) are thought to mediate repression and downstream activation by their association with binding partners that form dynamic protein complexes that elicit differing effects on translation depending on cell stage and interacting proteins. The cytoplasmic polyadenylation (CP) element, Pumilio binding element, and hexanucleotide polyadenylation signal are among the best understood motifs involved in CP, and translational regulation of stored transcripts as their binding partners have been relatively well‐characterized. Knowledge of CP in mammalian oocytes is discussed as well as novel approaches that can be used to enhance our understanding of the functional and contributing features to transcript CP and translational regulation during mammalian oocyte maturation. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-11-24T02:36:47.400443-05:
      DOI: 10.1002/wrna.1316
  • Roles for SUMO in pre‐mRNA processing
    • Abstract: When the small ubiquitin‐like modifier (SUMO)‐1 protein is localized on the genome, it is found on proteins bound to the promoters of the most highly active genes and on proteins bound to the DNA‐encoding exons. Inhibition of the SUMO‐1 modification leads to reductions in initiation of messenger RNA (mRNA) synthesis and splicing. In this review, we discuss what is known about the SUMOylation of factors involved in transcription initiation, pre‐mRNA processing, and polyadenylation. We suggest a mechanism by which SUMO modifications of factors at the promoters of high‐activity genes trigger the formation of an RNA polymerase II complex that coordinates and integrates the stimulatory signals for each process to catalyze an extremely high level of gene expression. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-11-13T00:06:40.988078-05:
      DOI: 10.1002/wrna.1318
  • The sweet side of RNA regulation: glyceraldehyde‐3‐phosphate
           dehydrogenase as a noncanonical RNA‐binding protein
    • Authors: Michael R. White; Elsa D. Garcin
      Abstract: The glycolytic protein, glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), has a vast array of extraglycolytic cellular functions, including interactions with nucleic acids. GAPDH has been implicated in the translocation of transfer RNA (tRNA), the regulation of cellular messenger RNA (mRNA) stability and translation, as well as the regulation of replication and gene expression of many single‐stranded RNA viruses. A growing body of evidence supports GAPDH–RNA interactions serving as part of a larger coordination between intermediary metabolism and RNA biogenesis. Despite the established role of GAPDH in nucleic acid regulation, it is still unclear how and where GAPDH binds to its RNA targets, highlighted by the absence of any conserved RNA‐binding sequences. This review will summarize our current understanding of GAPDH‐mediated regulation of RNA function. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-11-12T21:12:25.549178-05:
      DOI: 10.1002/wrna.1315
  • Trypanosome RNA editing: the complexity of getting U in and taking U out
    • Abstract: RNA editing, which adds sequence information to RNAs post‐transcriptionally, is a widespread phenomenon throughout eukaryotes. The most complex form of this process is the uridine (U) insertion/deletion editing that occurs in the mitochondria of kinetoplastid protists. RNA editing in these flagellates is specified by trans‐acting guide RNAs and entails the insertion of hundreds and deletion of dozens of U residues from mitochondrial RNAs to produce mature, translatable mRNAs. An emerging model indicates that the machinery required for trypanosome RNA editing is much more complicated than previously appreciated. A family of RNA editing core complexes (RECCs), which contain the required enzymes and several structural proteins, catalyze cycles of U insertion and deletion. A second, dynamic multiprotein complex, the Mitochondrial RNA Binding 1 (MRB1) complex, has recently come to light as another essential component of the trypanosome RNA editing machinery. MRB1 likely serves as the platform for kinetoplastid RNA editing, and plays critical roles in RNA utilization and editing processivity. MRB1 also appears to act as a hub for coordination of RNA editing with additional mitochondrial RNA processing events. This review highlights the current knowledge regarding the complex molecular machinery involved in trypanosome RNA editing. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-11-02T00:42:10.659256-05:
      DOI: 10.1002/wrna.1313
  • Issue information
    • PubDate: 2015-10-25T17:59:51.394232-05:
      DOI: 10.1002/wrna.1314
  • Prp40 and early events in splice site definition
    • Abstract: The alternative splicing (AS) of precursor messenger RNA (pre‐mRNA) is a tightly regulated process through which introns are removed to leave the resulting exons in the mRNA appropriately aligned and ligated. The AS of pre‐mRNA is a key mechanism for increasing the complexity of proteins encoded in the genome. In humans, more than 90% of genes undergo AS, underscoring the importance of this process in RNA biogenesis. As such, AS misregulation underlies multiple human diseases. The splicing reaction is catalyzed by the spliceosome, a highly dynamic complex that assembles at or near the intron/exon boundaries and undergoes sequential conformational and compositional changes during splicing. The initial recognition of splice sites defines the exons that are going to be removed, which is a critical step in the highly regulated splicing process. Although the available lines of evidence are increasing, the molecular mechanisms governing AS, including the initial interactions occurring at intron/exon boundaries, and the factors that modulate these critical connections by functioning as a scaffold for active‐site RNAs or proteins, remain poorly understood. In this review, we summarize the major hallmarks of the initial steps in the splicing process and the role of auxiliary factors that contribute to the assembly of the spliceosomal complex. We also discuss the role of the essential yeast Prp40 protein and its mammalian homologs in the specificity of this pre‐mRNA processing event. In addition, we provide the first exhaustive phylogenetic analysis of the molecular evolution of Prp40 family members. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-10-23T02:05:53.269404-05:
      DOI: 10.1002/wrna.1312
  • Satellite RNA pathogens of plants: impacts and origins—an RNA
           silencing perspective
    • Abstract: Viral satellite RNAs (satRNAs) are among the smallest RNA pathogens in plants. They have little or no protein‐coding capacity but can have a major impact on the host plants through trilateral interactions with helper viruses and host plants. Studies around the 1980s revealed much of what we know about satRNAs: they can affect helper virus accumulation, modulate helper virus‐induced disease symptoms, and induce their own symptoms with the assistance of helper viruses which depend on specific nucleotide sequences of their genome and host species. The molecular basis of these satRNA‐caused impacts and the origin of satRNAs have yet to be fully understood and revealed, but recent understanding of the antiviral RNA silencing pathways and advancement in RNA and DNA sequencing technologies have provided new avenues and opportunities to examine these unanswered questions. These RNA silencing‐based studies have revealed the existence of cross silencing between some satRNAs and helper viruses, the downregulation of helper virus‐encoded suppressor (VSR) of RNA silencing or inhibition/enhancement of VSR activity by satRNAs, the silencing of host‐encoded genes by satRNA‐derived small interfering RNA (siRNAs), and the presence of satRNA‐like small RNAs in uninfected host plants. These findings have provided alternative RNA silencing‐based models to explain the pathogenicity and origin of satRNAs. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-10-20T00:53:10.1655-05:00
      DOI: 10.1002/wrna.1311
  • Engineering RNA‐binding proteins with diverse activities
    • Authors: Huanhuan Wei; Zefeng Wang
      First page: 597
      Abstract: With generations of efforts to understand RNA functions in diverse cellular processes, RNA‐binding proteins (RBPs) have emerged to be one of the central players in regulating RNA‐related pathways. RBPs control almost all aspects of RNA processing via recognizing their RNA target(s). Most of these proteins have a modular configuration, with one or more RNA‐binding domain for target recognition and various functional modules to affect the metabolism and biological functions of RNA. Thus, engineering RNA‐binding factors with customized specificity and function is extremely useful in biological and medical research. In this review, we discuss the current advances in engineering RBPs that specifically bind to diverse targets, with emphasis on the design strategies and their applications as new biological tools in various aspects of RNA metabolism and function. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-08-28T18:37:53.957687-05:
      DOI: 10.1002/wrna.1296
  • Noncoding RNA control of cellular senescence
    • Authors: Kotb Abdelmohsen; Myriam Gorospe
      First page: 615
      Abstract: Senescent cells accumulate in normal tissues with advancing age and arise by long‐term culture of primary cells. Senescence develops following exposure to a range of stress‐causing agents and broadly influences the physiology and pathology of tissues, organs, and systems in the body. While many proteins are known to control senescence, numerous noncoding (nc)RNAs are also found to promote or repress the senescent phenotype. Here, we review the regulatory ncRNAs (primarily microRNAs and lncRNAs) identified to‐date as key modulators of senescence. We highlight the major senescent pathways (p53/p21 and pRB/p16), as well as the senescence‐associated secretory phenotype (SASP) and other senescence‐associated events governed by ncRNAs, and discuss the importance of understanding comprehensively the ncRNAs implicated in cell senescence. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-09-01T05:31:58.776754-05:
      DOI: 10.1002/wrna.1297
  • Linking aptamer‐ligand binding and expression platform folding in
           riboswitches: prospects for mechanistic modeling and design
    • First page: 631
      Abstract: The power of riboswitches in regulation of bacterial metabolism derives from coupling of two characteristics: recognition and folding. Riboswitches contain aptamers, which function as biosensors. Upon detection of the signaling molecule, the riboswitch transduces the signal into a genetic decision. The genetic decision is coupled to refolding of the expression platform, which is distinct from, although overlapping with, the aptamer. Early biophysical studies of riboswitches focused on recognition of the ligand by the aptamer‐an important consideration for drug design. A mechanistic understanding of ligand‐induced riboswitch RNA folding can further enhance riboswitch ligand design, and inform efforts to tune and engineer riboswitches with novel properties. X‐ray structures of aptamer/ligand complexes point to mechanisms through which the ligand brings together distal strand segments to form a P1 helix. Transcriptional riboswitches must detect the ligand and form this P1 helix within the timescale of transcription. Depending on the cell's metabolic state and cellular environmental conditions, the folding and genetic outcome may therefore be affected by kinetics of ligand binding, RNA folding, and transcriptional pausing, among other factors. Although some studies of isolated riboswitch aptamers found homogeneous, prefolded conformations, experimental, and theoretical studies point to functional and structural heterogeneity for nascent transcripts. Recently it has been shown that some riboswitch segments, containing the aptamer and partial expression platforms, can form binding‐competent conformers that incorporate an incomplete aptamer secondary structure. Consideration of the free energy landscape for riboswitch RNA folding suggests models for how these conformers may act as transition states—facilitating rapid, ligand‐mediated aptamer folding. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-09-11T23:52:09.926454-05:
      DOI: 10.1002/wrna.1300
  • Splicing noncoding RNAs from the inside out
    • Authors: Li Yang
      First page: 651
      Abstract: Eukaryotic precursor‐messenger RNAs (pre‐mRNAs) undergo splicing to remove intragenic regions (introns) and ligate expressed regions (exons) together. Unlike exons in the mature messenger RNAs (mRNAs) that are used for translation, introns that are spliced out of pre‐mRNAs were generally believed to lack function and to be degraded. However, recent studies have revealed that a large group of spliced introns can escape complete degradation and are processed to generate noncoding RNAs (ncRNAs), including different types of small RNAs, long‐noncoding RNAs, and circular RNAs. Strikingly, exonic sequences can be also back‐spliced from pre‐mRNAs to form stable circular RNAs. Together, the findings that ncRNAs can be spliced out of mRNA precursors not only expand the ever‐growing repertoire of ncRNAs that originate from different genomic regions, but also reveal the unexpected transcriptomic complexity and functional capacity of eukaryotic genomes. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-10-01T03:50:58.161499-05:
      DOI: 10.1002/wrna.1307
  • Roles of microRNAs and long‐noncoding RNAs in human immunodeficiency
           virus replication
    • Authors: Andrew P. Rice
      First page: 661
      Abstract: MicroRNAs (miRNAs) and long‐noncoding RNAs (lncRNAs) are involved in many biological processes, including viral replication. In this review, the role of miRNAs and lncRNAs in human immunodeficiency virus (HIV) replication will be discussed. The review focuses on miRNAs that target cellular proteins involved in HIV replication—proteins that mediate steps in the viral life cycle, as well as proteins of the innate immune system that inhibit HIV replication. Given the large number of miRNAs encoded in the human genome, as well as the large number of cellular proteins involved in HIV replication, the number of miRNAs identified to date that affect viral replication are certainly only the ‘tip of the iceberg’. The review also discusses two lncRNAs that are involved in HIV gene regulation—7SK RNA and NEAT1 RNA. 7SK RNA is involved in HIV Tat protein stimulation of RNA polymerase II elongation of the integrated provirus, while NEAT1 RNA is involved in HIV Rev protein export of incompletely spliced viral transcripts. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-09-22T09:35:05.015722-05:
      DOI: 10.1002/wrna.1308
  • Regulatory RNAs discovered in unexpected places
    • Authors: Jun Wei Pek; Katsutomo Okamura
      First page: 671
      Abstract: Recent studies have discovered both small and long noncoding RNAs (ncRNAs) encoded in unexpected places. These ncRNA genes were surprises at the time of their discovery, but many quickly became well‐accepted families of functional regulatory RNA species. Even after years of extensive gene annotation studies using high‐throughput sequencing technologies, new types of ncRNA genes continue to be discovered in unexpected places. We highlight ncRNAs that have atypical structures and that are encoded in what are generally considered ‘junk’ sequences, such as spacers and introns. We also discuss current bottlenecks in the approaches for identifying novel ncRNAs and the possibility that many remain to be discovered. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-10-01T03:49:52.132563-05:
      DOI: 10.1002/wrna.1309
  • RNA‐based regulation of transposon expression
    • Authors: Daniel Gebert; David Rosenkranz
      First page: 687
      Abstract: Throughout the domains of life, transposon activity represents a serious threat to genome integrity and evolution has realized different molecular mechanisms that aim to inhibit the transposition of mobile DNA. Small noncoding RNAs that function as guides for Argonaute effector proteins represent a key feature of so‐called RNA interference (RNAi) pathways and specialized RNAi pathways exist to repress transposon activity on the transcriptional and posttranscriptional level. Transposon transcription can be diminished by targeted DNA methylation or chromatin remodeling via repressive Histone modifications. Posttranscriptional transposon silencing bases on degradation of transposon transcripts to prevent either reverse transcription followed by genomic reintegration or translation into proteins that mediate the transposition process. In plants, Argonaute‐like proteins guided by short interfering RNAs (siRNAs) are essential for transposon repression on the epigenetic and posttranscriptional level. In the germline of animals, these tasks are often assumed by a second subclass of Argonaute proteins referred to as Piwi‐like proteins, which bind a distinct class of small noncoding RNAs named piwi‐interacting RNAs (piRNAs). Though the principals of RNAi pathways are essentially the same in all eukaryotic organisms, remarkable differences can be observed even in closely related species reflecting the astonishing plasticity and diversity of these pathways. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-10-06T04:50:15.344387-05:
      DOI: 10.1002/wrna.1310
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