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Journal Cover Wiley Interdisciplinary Reviews : RNA
   [3 followers]  Follow    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Online) 1757-7012
     Published by John Wiley and Sons Homepage  [1604 journals]   [SJR: 2.692]   [H-I: 10]
  • Small RNAs with big implications: new insights into H/ACA snoRNA function
           and their role in human disease
    • Authors: Mary McMahon; Adrian Contreras, Davide Ruggero
      Abstract: A myriad of structurally and functionally diverse noncoding RNAs (ncRNAs) have recently been implicated in numerous human diseases including cancer. Small nucleolar RNAs (snoRNAs), the most abundant group of intron‐encoded ncRNAs, are classified into two families (box C/D snoRNAs and box H/ACA snoRNAs) and are required for post‐transcriptional modifications on ribosomal RNA (rRNA). There is now a growing appreciation that nucleotide modifications on rRNA may impart regulatory potential to the ribosome; however, the functional consequence of site‐specific snoRNA‐guided modifications remains poorly defined. Discovered almost 20 years ago, H/ACA snoRNAs are required for the conversion of specific uridine residues to pseudouridine on rRNA. Interestingly, recent reports indicate that the levels of subsets of H/ACA snoRNAs required for pseudouridine modifications at specific sites on rRNA are altered in several diseases, particularly cancer. In this review, we describe recent advances in understanding the downstream consequences of H/ACA snoRNA‐guided modifications on ribosome function, discuss the possible mechanism by which H/ACA snoRNAs may be regulated, and explore prospective expanding functions of H/ACA snoRNAs. Furthermore, we discuss the potential biological implications of alterations in H/ACA snoRNA expression in several human diseases. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-10-31T13:32:30.900167-05:
      DOI: 10.1002/wrna.1266
       
  • An introduction to recurrent nucleotide interactions in RNA
    • Authors: Blake A. Sweeney; Poorna Roy, Neocles B. Leontis
      Pages: n/a - n/a
      Abstract: RNA secondary structure diagrams familiar to molecular biologists summarize at a glance the folding of RNA chains to form Watson–Crick paired double helices. However, they can be misleading: First of all, they imply that the nucleotides in loops and linker segments, which can amount to 35% to 50% of a structured RNA, do not significantly interact with other nucleotides. Secondly, they give the impression that RNA molecules are loosely organized in three‐dimensional (3D) space. In fact, structured RNAs are compactly folded as a result of numerous long‐range, sequence‐specific interactions, many of which involve loop or linker nucleotides. Here, we provide an introduction for students and researchers of RNA on the types, prevalence, and sequence variations of inter‐nucleotide interactions that structure and stabilize RNA 3D motifs and architectures, using Escherichia coli (E. coli) 16S ribosomal RNA as a concrete example. The picture that emerges is that almost all nucleotides in structured RNA molecules, including those in nominally single‐stranded loop or linker regions, form specific interactions that stabilize functional structures or mediate interactions with other molecules. The small number of noninteracting, ‘looped‐out’ nucleotides make it possible for the RNA chain to form sharp turns. Base‐pairing is the most specific interaction in RNA as it involves edge‐to‐edge hydrogen bonding (H‐bonding) of the bases. Non‐Watson–Crick base pairs are a significant fraction (30% or more) of base pairs in structured RNAs. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-10-29T13:18:19.21524-05:0
      DOI: 10.1002/wrna.1258
       
  • Understanding the potential of hepatitis C virus internal ribosome entry
           site domains to modulate translation initiation via their structure and
           function
    • Authors: Anas Khawaja; Vaclav Vopalensky, Martin Pospisek
      Pages: n/a - n/a
      Abstract: Translation initiation in the hepatitis C virus (HCV) occurs through a cap‐independent mechanism that involves an internal ribosome entry site (IRES) capable of interacting with and utilizing the eukaryotic translational machinery. In this review, we focus on the structural configuration of the different HCV IRES domains and the impact of IRES primary sequence variations on secondary structure conservation and function. In some cases, multiple mutations, even those scattered across different domains, led to restoration of the translational activity of the HCV IRES, although the individual occurrences of these mutations were found to be deleterious. We propose that such observation may be attributed to probable long‐range inter‐ and/or intra‐domain functional interactions. The precise functioning of the HCV IRES requires the specific interaction of its domains with ribosomal subunits and a subset of eukaryotic translation initiation factors (eIFs). The structural conformation, sequence preservation and variability, and translational machinery association with the HCV IRES regions are also thoroughly discussed, along with other factors that can affect and influence the formation of translation initiation complexes. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-10-28T10:03:16.737631-05:
      DOI: 10.1002/wrna.1268
       
  • An overview of pre‐ribosomal RNA processing in eukaryotes
    • Authors: Anthony K. Henras; Célia Plisson‐Chastang, Marie‐Françoise O'Donohue, Anirban Chakraborty, Pierre‐Emmanuel Gleizes
      Pages: n/a - n/a
      Abstract: Ribosomal RNAs are the most abundant and universal noncoding RNAs in living organisms. In eukaryotes, three of the four ribosomal RNAs forming the 40S and 60S subunits are borne by a long polycistronic pre‐ribosomal RNA. A complex sequence of processing steps is required to gradually release the mature RNAs from this precursor, concomitant with the assembly of the 79 ribosomal proteins. A large set of trans‐acting factors chaperone this process, including small nucleolar ribonucleoparticles. While yeast has been the gold standard for studying the molecular basis of this process, recent technical advances have allowed to further define the mechanisms of ribosome biogenesis in animals and plants. This renewed interest for a long‐lasting question has been fueled by the association of several genetic diseases with mutations in genes encoding both ribosomal proteins and ribosome biogenesis factors, and by the perspective of new anticancer treatments targeting the mechanisms of ribosome synthesis. A consensus scheme of pre‐ribosomal RNA maturation is emerging from studies in various kinds of eukaryotic organisms. However, major differences between mammalian and yeast pre‐ribosomal RNA processing have recently come to light. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-10-27T01:11:44.674174-05:
      DOI: 10.1002/wrna.1269
       
  • Issue information
    • PubDate: 2014-10-21T08:54:37.286248-05:
      DOI: 10.1002/wrna.1271
       
  • Processing of preribosomal RNA in Saccharomyces cerevisiae
    • Authors: Antonio Fernández‐Pevida; Dieter Kressler, Jesús de la Cruz
      Abstract: Most, if not all RNAs, are transcribed as precursors that require processing to gain functionality. Ribosomal RNAs (rRNA) from all organisms undergo both exo‐ and endonucleolytic processing. Also, in all organisms, rRNA processing occurs inside large preribosomal particles and is coupled to nucleotide modification, folding of the precursor rRNA (pre‐rRNA), and assembly of the ribosomal proteins (r‐proteins). In this review, we focus on the processing pathway of pre‐rRNAs of cytoplasmic ribosomes in the yeast Saccharomyces cerevisiae, without doubt, the organism where this pathway is best characterized. We summarize the current understanding of the rRNA maturation process, particularly focusing on the pre‐rRNA processing sites, the enzymes responsible for the cleavage or trimming reactions and the different mechanisms that monitor and regulate the pathway. Strikingly, the overall order of the various processing steps is reasonably well conserved in eukaryotes, perhaps reflecting common principles for orchestrating the concomitant events of pre‐rRNA processing and ribosome assembly. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-10-18T05:01:30.990362-05:
      DOI: 10.1002/wrna.1267
       
  • Ilf3 and NF90 functions in RNA biology
    • Authors: Sandrine Castella; Rozenn Bernard, Mélanie Corno, Aurélie Fradin, Jean‐Christophe Larcher
      Abstract: Double‐stranded RNA‐binding proteins (DRBPs) are known to regulate many processes of RNA metabolism due, among others, to the presence of double‐stranded RNA (dsRNA)‐binding motifs (dsRBMs). Among these DRBPs, Interleukin enhancer‐binding factor 3 (Ilf3) and Nuclear Factor 90 (NF90) are two ubiquitous proteins generated by mutually exclusive and alternative splicings of the Ilf3 gene. They share common N‐terminal and central sequences but display specific C‐terminal regions. They present a large heterogeneity generated by several post‐transcriptional and post‐translational modifications involved in their subcellular localization and biological functions. While Ilf3 and NF90 were first identified as activators of gene expression, they are also implicated in cellular processes unrelated to RNA metabolism such as regulation of the cell cycle or of enzymatic activites. The implication of Ilf3 and NF90 in RNA biology will be discussed with a focus on eukaryote transcription and translation regulation, on viral replication and translation as well as on noncoding RNA field. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-10-18T04:58:52.572364-05:
      DOI: 10.1002/wrna.1270
       
  • Control of cell migration through mRNA localization and local translation
    • Authors: Guoning Liao; Lisa Mingle, Livingston Van De Water, Gang Liu
      Abstract: Cell migration plays an important role in many normal and pathological functions such as development, wound healing, immune defense, and tumor metastasis. Polarized migrating cells exhibit asymmetric distribution of many cytoskeletal proteins, which is believed to be critical for establishing and maintaining cell polarity and directional cell migration. To target these proteins to the site of function, cells use a variety of mechanisms such as protein transport and messenger RNA (mRNA) localization‐mediated local protein synthesis. In contrast to the former which is intensively investigated and relatively well understood, the latter has been understudied and relatively poorly understood. However, recent advances in the study of mRNA localization and local translation have demonstrated that mRNA localization and local translation are specific and effective ways for protein localization and are crucial for embryo development, neuronal function, and many other cellular processes. There are excellent reviews on mRNA localization, transport, and translation during development and other cellular processes. This review will focus on mRNA localization‐mediated local protein biogenesis and its impact on somatic cell migration. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-09-28T17:58:27.270557-05:
      DOI: 10.1002/wrna.1265
       
  • Effects of messenger RNA structure and other translational control
           mechanisms on major histocompatibility complex‐I mediated antigen
           presentation
    • Authors: Pierre Murat; Judy Tellam
      Abstract: Effective T‐cell surveillance of antigen‐presenting cells is dependent on the expression of an array of antigenic peptides bound to major histocompatibility complex (MHC) class I (MHC‐I) or class II (MHC‐II) molecules. Pathogens co‐evolving with their hosts exploit crucial translational regulatory mechanisms in order to evade host immune recognition and thereby sustain their infection. Evasion strategies that downregulate viral protein synthesis and thereby restrict antigen presentation to cytotoxic T‐cells through the endogenous MHC‐I pathway have been implicated in the pathogenesis of viral‐associated malignancies. An understanding of the mechanisms by which messenger RNA (mRNA) structure modulates both viral mRNA translation and the antigen processing machinery to escape immune surveillance, will stimulate the development of alternative therapeutic strategies focused on RNA‐directed drugs designed to enhance immune responses against infected cells. In this review, we discuss regulatory aspects of the MHC‐I pathway and summarize current knowledge of the role attributed by mRNA structure and other translational regulatory mechanisms in immune evasion. In particular we highlight the impact of recently identified G‐quadruplex structures within virally encoded transcripts as unique regulatory signals for translational control and antigen presentation. Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.
      PubDate: 2014-09-26T10:07:27.094592-05:
      DOI: 10.1002/wrna.1262
       
  • Insights into the U1 small nuclear ribonucleoprotein complex superfamily
    • Authors: J Guiro; D O'Reilly
      Abstract: The 164 bp U1 small nuclear (sn) RNA is one of the most abundant noncoding (nc) RNA in human cells, estimated to be in the region of 106 copies/cell. Although best known for its role in pre‐messenger RNA (mRNA) splicing events, research over the past 20 years has revealed diverse functions of this ncRNA in mammalian cell types. Excellent reviews exist detailing the role of U1 snRNA in pre‐mRNA splicing events. This review highlights what is currently known regarding the additional roles, snRNP composition, expression profiles, and the genomic organization of this ncRNA. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-09-26T07:38:13.331379-05:
      DOI: 10.1002/wrna.1257
       
  • The influence of Argonaute proteins on alternative RNA splicing
    • Authors: Eric Batsché; Maya Ameyar‐Zazoua
      Abstract: Alternative splicing of precursor RNAs is an important process in multicellular species because it impacts several aspects of gene expression: from the increase of protein repertoire to the level of expression. A large body of evidences demonstrates that factors regulating chromatin and transcription impact the outcomes of alternative splicing. Argonaute (AGO) proteins were known to play key roles in the regulation of gene expression at the post‐transcriptional level. More recently, their role in the nucleus of human somatic cells has emerged. Here, we will discuss some of the nuclear functions of AGO, with special emphasis on alternative splicing. The AGO‐mediated modulation of alternative splicing is based on several properties of these proteins: their binding to transcripts on chromatin and their interactions with many proteins, especially histone tail‐modifying enzymes, HP1γ and splicing factors. AGO proteins may favor a decrease in the RNA‐polymerase II kinetics at actively transcribed genes leading to the modulation of alternative splicing decisions. They could also influence alternative splicing through their interaction with core components of the splicing machinery and several splicing factors. We will discuss the modes of AGO recruitment on chromatin at active genes. We suggest that long intragenic antisense transcripts (lincRNA) might be an important feature of genes containing splicing events regulated by AGO. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-09-25T14:12:37.715526-05:
      DOI: 10.1002/wrna.1264
       
  • Cotranscriptional events in eukaryotic ribosome synthesis
    • Authors: Tomasz W. Turowski; David Tollervey
      Abstract: Eukaryotic ribosomes are synthesized in a complex, multistep pathway. This begins with transcription of the rDNA genes by a specialized RNA polymerase, accompanied by the cotranscriptional binding of large numbers of ribosome synthesis factors, small nucleolar RNAs and ribosomal proteins. Cleavage of the nascent transcript releases the early pre‐40S and pre‐60S particles, which acquire export competence in the nucleoplasm prior to translocation through the nuclear pore complexes and final maturation to functional ribosomal subunits in the cytoplasm. This review will focus on the many and complex interactions occurring during pre‐rRNA synthesis, particularly in budding yeast in which the pathway is best understood. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-08-29T14:43:19.204744-05:
      DOI: 10.1002/wrna.1263
       
  • The RNAissance family: SR proteins as multifaceted regulators of gene
           expression
    • Authors: Jonathan M. Howard; Jeremy R. Sanford
      Abstract: Serine and arginine‐rich (SR) proteins play multiple roles in the eukaryotic gene expression pathway. Initially described as constitutive and alternative splicing factors, now it is clear that SR proteins are key determinants of exon identity and function as molecular adaptors, linking the pre‐messenger RNA (pre‐mRNA) to the splicing machinery. In addition, now SR proteins are implicated in many aspects of mRNA and noncoding RNA (ncRNA) processing well beyond splicing. These unexpected roles, including RNA transcription, export, translation, and decay, may prove to be the rule rather than the exception. To simply define, this family of RNA‐binding proteins as splicing factors belies the broader roles of SR proteins in post‐transcriptional gene expression. Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.
      PubDate: 2014-08-22T18:18:44.677454-05:
      DOI: 10.1002/wrna.1260
       
  • RNA triplexes: from structural principles to biological and biotech
           applications
    • Authors: Gitali Devi; Yuan Zhou, Zhensheng Zhong, Desiree‐Faye Kaixin Toh, Gang Chen
      Abstract: The diverse biological functions of RNA are determined by the complex structures of RNA stabilized by both secondary and tertiary interactions. An RNA triplex is an important tertiary structure motif that is found in many pseudoknots and other structured RNAs. A triplex structure usually forms through tertiary interactions in the major or minor groove of a Watson–Crick base‐paired stem. A major‐groove RNA triplex structure is stable in isolation by forming consecutive major‐groove base triples such as U·A‐U and C+·G‐C. Minor‐groove RNA triplexes, e.g., A‐minor motif triplexes, are found in almost all large structured RNAs. As double‐stranded RNA stem regions are often involved in biologically important tertiary triplex structure formation and protein binding, the ability to sequence specifically target any desired RNA duplexes by triplex formation would have great potential for biomedical applications. Programmable chemically modified triplex‐forming oligonucleotides (TFOs) and triplex‐forming peptide nucleic acids (PNAs) have been developed to form TFO·RNA2 and PNA·RNA2 triplexes, respectively, with enhanced binding affinity and sequence specificity at physiological conditions. Here, we (1) provide an overview of naturally occurring RNA triplexes, (2) summarize the experimental methods for studying triplexes, and (3) review the development of TFOs and triplex‐forming PNAs for targeting an HIV‐1 ribosomal frameshift‐inducing RNA, a bacterial ribosomal A‐site RNA, and a human microRNA hairpin precursor, and for inhibiting the RNA–protein interactions involving human RNA‐dependent protein kinase and HIV‐1 viral protein Rev. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-08-22T04:57:21.390679-05:
      DOI: 10.1002/wrna.1261
       
  • CLP1 as a novel player in linking tRNA splicing to neurodegenerative
           disorders
    • Authors: Stefan Weitzer; Toshikatsu Hanada, Josef M. Penninger, Javier Martinez
      Abstract: Defects in RNA metabolic pathways are well‐established causes for neurodegenerative disorders. Several mutations in genes involved in pre‐messenger RNA (pre‐mRNA) and tRNA metabolism, RNA stability and protein translation have been linked to motor neuron diseases. Our study on a mouse carrying a catalytically inactive version of the RNA kinase CLP1, a component of the tRNA splicing endonuclease complex, revealed a neurological disorder characterized by progressive loss of lower spinal motor neurons. Surprisingly, mutant mice accumulate a novel class of tRNA‐derived fragments. In addition, patients with homozygous missense mutations in CLP1 (R140H) were recently identified who suffer from severe motor‐sensory defects, cortical dysgenesis and microcephaly, and exhibit alterations in transfer RNA (tRNA) splicing. Here, we review functions of CLP1 in different RNA pathways and provide hypotheses on the role of the tRNA splicing machinery in the generation of tRNA fragments and the molecular links to neurodegenerative disorders. We further immerse the biology of tRNA splicing into topics of (t)RNA metabolism and oxidative stress, putting forward the idea that defects in tRNA processing leading to tRNA fragment accumulation might trigger the development of neurodegenerative diseases. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-08-20T09:42:52.013605-05:
      DOI: 10.1002/wrna.1255
       
  • microRNAs: role in leukemia and their computational perspective
    • Authors: Ankur Omer; Poonam Singh, Navneet Kumar Yadav, Rama Kant Singh
      Pages: n/a - n/a
      Abstract: MicroRNAs (miRNAs) belong to the family of noncoding RNAs (ncRNAs) and had gained importance due to its role in complex biochemical pathways. Changes in the expression of protein coding genes are the major cause of leukemia. Role of miRNAs as tumor suppressors has provided a new insight in the field of leukemia research. Particularly, the miRNAs mediated gene regulation involves the modulation of multiple mRNAs and cooperative action of different miRNAs to regulate a particular gene expression. This highly complex array of regulatory pathway network indicates the great possibility in analyzing and identifying novel findings. Owing to the conventional, slow experimental identification process of miRNAs and their targets, the last decade has witnessed the development of a large amount of computational approaches to deal with the complex interrelations present within biological systems. This article describes the various roles played by miRNAs in regulating leukemia and the role of computational approaches in exploring new possibilities. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-08-15T16:30:40.780936-05:
      DOI: 10.1002/wrna.1256
       
  • RNA structural analysis by evolving SHAPE chemistry
    • Authors: Robert C. Spitale; Ryan A. Flynn, Eduardo A. Torre, Eric T. Kool, Howard Y. Chang
      Pages: n/a - n/a
      Abstract: RNA is central to the flow of biological information. From transcription to splicing, RNA localization, translation, and decay, RNA is intimately involved in regulating every step of the gene expression program, and is thus essential for health and understanding disease. RNA has the unique ability to base‐pair with itself and other nucleic acids to form complex structures. Hence the information content in RNA is not simply its linear sequence of bases, but is also encoded in complex folding of RNA molecules. A general chemical functionality that all RNAs have is a 2′‐hydroxyl group in the ribose ring, and the reactivity of the 2′‐hydroxyl in RNA is gated by local nucleotide flexibility. In other words, the 2′‐hydroxyl is reactive at single‐stranded and conformationally flexible positions but is unreactive at nucleotides constrained by base‐pairing. Recent efforts have been focused on developing reagents that modify RNA as a function of RNA 2′ hydroxyl group reactivity. Such RNA structure probing techniques can be read out by primer extension in experiments termed RNA SHAPE (selective 2′‐ hydroxyl acylation and primer extension). Herein, we describe the efforts devoted to the design and utilization of SHAPE probes for characterizing RNA structure. We also describe current technological advances that are being applied to utilize SHAPE chemistry with deep sequencing to probe many RNAs in parallel. The merging of chemistry with genomics is sure to open the door to genome‐wide exploration of RNA structure and function. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-08-15T15:53:40.751254-05:
      DOI: 10.1002/wrna.1253
       
  • Interrelations between translation and general mRNA degradation in yeast
    • Authors: Susanne Huch; Tracy Nissan
      Pages: n/a - n/a
      Abstract: Messenger RNA (mRNA) degradation is an important element of gene expression that can be modulated by alterations in translation, such as reductions in initiation or elongation rates. Reducing translation initiation strongly affects mRNA degradation by driving mRNA toward the assembly of a decapping complex, leading to decapping. While mRNA stability decreases as a consequence of translational inhibition, in apparent contradiction several external stresses both inhibit translation initiation and stabilize mRNA. A key difference in these processes is that stresses induce multiple responses, one of which stabilizes mRNAs at the initial and rate-limiting step of general mRNA decay. Because this increase in mRNA stability is directly induced by stress, it is independent of the translational effects of stress, which provide the cell with an opportunity to assess its response to changing environmental conditions. After assessment, the cell can store mRNAs, reinitiate their translation or, alternatively, embark on a program of enhanced mRNA decay en masse. Finally, recent results suggest that mRNA decay is not limited to non-translating messages and can occur when ribosomes are not initiating but are still elongating on mRNA. This review will discuss the models for the mechanisms of these processes and recent developments in understanding the relationship between translation and general mRNA degradation, with a focus on yeast as a model system. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-06-18T07:55:27.467807-05:
      DOI: 10.1002/wrna.1244
       
  • Small noncoding RNAs and male infertility
    • Authors: Lan‐Tao Gou; Peng Dai, Mo‐Fang Liu
      First page: 733
      Abstract: Small noncoding RNAs (ncRNAs) are a novel class of gene regulators that modulate gene expression at transcriptional, post‐transcriptional, and epigenetic levels, and they play crucial roles in almost all cellular processes in eukaryotes. Recent studies have indicated that several types of small noncoding RNAs, including microRNAs (miRNAs), endo‐small interference RNAs (endo‐siRNAs), and Piwi‐interacting RNAs (piRNAs), are expressed in the male germline and are required for spermatogenesis in animals. In this review, we summarize the recent knowledge of these small noncoding RNAs in male germ cells and their biological functions and mechanisms of action in animal spermatogenesis. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-07-08T06:43:41.153365-05:
      DOI: 10.1002/wrna.1252
       
  • The regulatory potential of upstream open reading frames in eukaryotic
           gene expression
    • Authors: Klaus Wethmar
      First page: 765
      Abstract: Upstream open reading frames (uORFs) are prevalent cis‐regulatory sequence elements in the transcript leader sequences (TLSs) of eukaryotic mRNAs. The majority of uORFs is considered to repress downstream translation by the consumption of functional pre‐initiation complexes or by inhibiting unrestrained progression of the ribosome. Under distinct conditions, specific uORF properties or sequential arrangements of uORFs can oppositely confer enhanced translation of the main coding sequence, designating uORFs as versatile modifiers of gene expression. Ribosome profiling and proteomic studies demonstrated widespread translational activity at AUG‐ and non‐AUG‐initiated uORFs in eukaryotic transcriptomes from yeast to human and several reports linked defective uORF‐mediated translational control to the development of human diseases. This review summarizes the structural features affecting uORF‐mediated translational control in eukaryotes and describes the highly divergent mechanisms of uORF regulation that result in repression or induction of downstream protein translation. For further resources related to this article, please visit the WIREs website. Conflict of interest: The author has declared no conflicts of interest for this article.
      PubDate: 2014-07-03T10:27:11.451576-05:
      DOI: 10.1002/wrna.1245
       
  • Novel viral translation strategies
    • Authors: Hilda HT Au; Eric Jan
      First page: 779
      Abstract: Viral genomes are compact and encode a limited number of proteins. Because they do not encode components of the translational machinery, viruses exhibit an absolute dependence on the host ribosome and factors for viral messenger RNA (mRNA) translation. In order to recruit the host ribosome, viruses have evolved unique strategies to either outcompete cellular transcripts that are efficiently translated by the canonical translation pathway or to reroute translation factors and ribosomes to the viral genome. Furthermore, viruses must evade host antiviral responses and escape immune surveillance. This review focuses on some recent major findings that have revealed unconventional strategies that viruses utilize, which include usurping the host translational machinery, modulating canonical translation initiation factors to specifically enhance or repress overall translation for the purpose of viral production, and increasing viral coding capacity. The discovery of these diverse viral strategies has provided insights into additional translational control mechanisms and into the viral host interactions that ensure viral protein synthesis and replication. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-07-08T07:21:11.265553-05:
      DOI: 10.1002/wrna.1246
       
  • Structure and function of pseudoknots involved in gene expression control
    • Authors: Alla Peselis; Alexander Serganov
      First page: 803
      Abstract: Natural RNA molecules can have a high degree of structural complexity but even the most complexly folded RNAs are assembled from simple structural building blocks. Among the simplest RNA elements are double‐stranded helices that participate in the formation of different folding topologies and constitute the major fraction of RNA structures. One common folding motif of RNA is a pseudoknot, defined as a bipartite helical structure formed by base‐pairing of the apical loop in the stem‐loop structure with an outside sequence. Pseudoknots constitute integral parts of the RNA structures essential for various cellular activities. Among many functions of pseudoknotted RNAs is feedback regulation of gene expression, carried out through specific recognition of various molecules. Pseudoknotted RNAs autoregulate ribosomal and phage protein genes in response to downstream encoded proteins, while many metabolic and transport genes are controlled by cellular metabolites interacting with pseudoknotted RNA elements from the riboswitch family. Modulation of some genes also depends on metabolite‐induced messenger RNA (mRNA) cleavage performed by pseudoknotted ribozymes. Several regulatory pseudoknots have been characterized biochemically and structurally in great detail. These studies have demonstrated a plethora of pseudoknot‐based folds and have begun uncovering diverse molecular principles of the ligand‐dependent gene expression control. The pseudoknot‐mediated mechanisms of gene control and many unexpected and interesting features of the regulatory pseudoknots have significantly advanced our understanding of the genetic circuits and laid the foundation for modulation of their outcomes. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-07-08T07:34:37.61093-05:0
      DOI: 10.1002/wrna.1247
       
  • The role of microRNA in resistance to breast cancer therapy
    • Authors: Neil M. Robertson; Mehmet V. Yigit
      First page: 823
      Abstract: MicroRNAs (miRNAs) are small noncoding RNA molecules with big implications in cancer. The abnormal expression of specific miRNAs has been linked to development of many cancer types. Dysregulated miRNAs play a significant role in proliferation, invasion, differentiation, apoptosis, and resistance of various cancer cells, and considered as oncogenes or tumor‐suppressor genes. Findings have shown abnormal expression of specific miRNAs in breast tumors is a strong indication about the resistance to conventional cancer therapy methods. Acquired cancer resistance is a complex, multifactorial occurrence that requires various mechanisms and processes, however, recent studies have suggested that resistance may be linked to treatment‐induced dysregulation of miRNAs. This dysregulation of miRNAs can affect the protein expression in cells, the ability for anti‐cancer drugs to reach their targets within cells, and the apoptotic pathways. Controlling the expression of these miRNAs alters the resistant phenotype of breast cancer to a nonresistant one. This review focuses on the role of dysregulated miRNAs in breast cancer that are linked to resistance against chemo‐, radiation, hormone, and targeted therapies. Finally, the role of miRNAs in breast cancer metastasis is briefly discussed. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-07-08T07:34:31.546054-05:
      DOI: 10.1002/wrna.1248
       
  • Noncoding RNAs and the borders of heterochromatin
    • Authors: Allison L. Cohen; Songtao Jia
      First page: 835
      Abstract: Eukaryotic genomes contain long stretches of repetitive DNA sequences, which are the preferred sites for the assembly of heterochromatin structures. The formation of heterochromatin results in highly condensed chromosomal domains that limit the accessibility of DNA to the transcription and recombination machinery to maintain genome stability. Heterochromatin has the tendency to spread, and the formation of boundaries that block heterochromatin spreading is required to maintain stable gene expression patterns. Recent work has suggested that noncoding RNAs (ncRNAs) are involved in regulating boundary formation in addition to their well‐established roles in chromatin regulation. Here, we present a review of our current understanding of the involvement of ncRNA at the boundaries of heterochromatin, highlighting their mechanisms of action in different settings. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-07-09T14:10:37.517848-05:
      DOI: 10.1002/wrna.1249
       
  • Not miR‐ly micromanagers: the functions and regulatory networks of
           microRNAs in mammalian skin
    • Authors: Kent Riemondy; Jaimee E Hoefert, Rui Yi
      First page: 849
      Abstract: The microRNA (miRNA) pathway is a widespread mechanism of post‐transcriptional gene regulation in eukaryotic cells. In animals, each miRNA species can regulate hundreds of protein‐coding genes, resulting in pervasive functions for miRNAs in numerous cellular processes. Since the identification of the first mammalian miRNA, the function of miRNAs in mammals has been a topic of great interest, both because of the versatile roles of miRNAs in biological systems, as well as the clinical potential of these regulatory RNAs. With well‐defined cell lineages and the availability of versatile tools for both in vivo and in vitro studies, mammalian skin has emerged as an important system in which to examine miRNAs' functions in adult tissues. In this review, we discuss recent insights into the functions and regulatory networks of miRNAs in mammals, with a specific focus on murine skin development as a model system. We first introduce functional analyses of the miRNA biogenesis pathway in the skin, then highlight the functions of individual miRNAs in skin development, followed by an examination of miRNA roles in skin stress responses. We finish with a discussion of miRNA regulatory networks and emphasize future challenges and emerging technologies that permit the genome‐wide study of miRNA functions and regulatory mechanisms in mammalian skin. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-07-09T14:10:35.411882-05:
      DOI: 10.1002/wrna.1250
       
  • Novel roles of the CCR4–NOT complex
    • Authors: Clément Chapat; Laura Corbo
      First page: 883
      Abstract: The CCR4–NOT complex is a multi‐subunit protein complex evolutionarily conserved across eukaryotes which regulates several aspects of gene expression. A fascinating model is emerging in which this complex acts as a regulation platform, controlling gene products ‘from birth to death’ through the coordination of different cellular machineries involved in diverse cellular functions. Recently the CCR4–NOT functions have been extended to the control of the innate immune response through the regulation of interferon signaling. Thus, a more comprehensive picture of how CCR4–NOT allows the rapid adaptation of cells to external stress, from transcription to mRNA and protein decay, is presented and discussed here. Overall, CCR4–NOT permits the efficient and rapid adaptation of cellular gene expression in response to changes in environmental conditions and stimuli. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
      PubDate: 2014-07-08T07:14:19.330063-05:
      DOI: 10.1002/wrna.1254
       
 
 
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