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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  [1598 journals]
  • Functionalities of expressed messenger RNAs revealed from mutant
    • Abstract: Total messenger RNAs mRNAs that are produced from a given gene under a certain set of conditions include both functional and nonfunctional transcripts. The high prevalence of nonfunctional mRNAs that have been detected in cells has raised questions regarding the functional implications of mRNA expression patterns and divergences. Phenotypes that result from the mutagenesis of protein‐coding genes have provided the most straightforward descriptions of gene functions, and such data obtained from model organisms have facilitated investigations of the functionalities of expressed mRNAs. Mutant phenotype data from mouse tissues have revealed various attributes of functional mRNAs, including tissue‐specificity, strength of expression, and evolutionary conservation. In addition, the role that mRNA expression evolution plays in driving morphological evolution has been revealed from studies designed to exploit morphological and physiological phenotypes of mouse mutants. Investigations into yeast essential genes (defined by an absence of colony growth after gene deletion) have further described gene regulatory strategies that reduce protein expression noise by mediating the rates of transcription and translation. In addition to the functional significance of expressed mRNAs as described in the abovementioned findings, the functionalities of other type of RNAs (i.e., noncoding RNAs) remain to be characterized with systematic mutations and phenotyping of the DNA regions that encode these RNA molecules. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-01-07T21:26:06.192755-05:
      DOI: 10.1002/wrna.1329
  • The role of the ribosome in the regulation of longevity and lifespan
    • Authors: Alyson W. MacInnes
      Abstract: The most energy‐consuming process that a cell must undertake to stay viable is the continuous biogenesis of ribosomes for the translation of RNA into protein. Given the inextricable links between energy consumption and cellular lifespan, it is not surprising that mutations and environmental cues that reduce ribosome biogenesis result in an extension of eukaryotic lifespan. This review goes into detail describing recent discoveries of different and often unexpected elements that play a role in the regulation of longevity by virtue of their ribosome biogenesis functions. These roles include controlling the transcription and processing of ribosomal RNA (rRNA), the translation of ribosomal protein (RP) genes, and the number of ribosomes overall. Together these findings suggest that a fundamental mechanism across eukaryotic species for extending lifespan is to slow down or halt the expenditure of cellular energy that is normally absorbed by the manufacturing and assembly of new ribosomes. For further resources related to this article, please visit the WIREs website.
      PubDate: 2016-01-05T23:38:34.246155-05:
      DOI: 10.1002/wrna.1325
  • Diverse roles of the nucleic acid‐binding protein KHSRP in cell
           differentiation and disease
    • Abstract: The single‐stranded nucleic acid‐binding protein KHSRP (KH‐type splicing regulatory protein) modulates RNA life and gene expression at various levels. KHSRP controls important cellular functions as different as proliferation, differentiation, metabolism, and response to infectious agents. We summarize and discuss experimental evidence providing a potential link between changes in KHSRP expression/function and human diseases including neuromuscular disorders, obesity, type II diabetes, and cancer. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-12-27T23:29:31.925372-05:
      DOI: 10.1002/wrna.1327
  • ADAR1, inosine and the immune sensing system: distinguishing self from
    • Authors: Brian J. Liddicoat; Alistair M. Chalk, Carl R. Walkley
      Abstract: The conversion of genomically encoded adenosine to inosine in dsRNA is termed as A‐to‐I RNA editing. This process is catalyzed by two of the three mammalian ADAR proteins (ADAR1 and ADAR2) both of which have essential functions for normal organismal homeostasis. The phenotype of ADAR2 deficiency can be primarily ascribed to a lack of site‐selective editing of a single transcript in the brain. In contrast, the biology and substrates responsible for the Adar1−/− phenotype have remained more elusive. Several recent studies have identified that a feature of absence or reductions of ADAR1 activity, conserved across human and mouse models, is a profound activation of interferon‐stimulated gene signatures and innate immune responses. Further analysis of this observation has lead to the conclusion that editing by ADAR1 is required to prevent activation of the cytosolic innate immune system, primarily focused on the dsRNA sensor MDA5 and leading to downstream signaling via MAVS. The delineation of this mechanism places ADAR1 at the interface between the cells ability to differentiate self‐ from non‐self dsRNA. Based on MDA5 dsRNA recognition requisites, the mechanism indicates that the type of dsRNA must fulfil a particular structural characteristic, rather than a sequence‐specific requirement. While additional studies are required to molecularly verify the genetic model, the observations to date collectively identify A‐to‐I editing by ADAR1 as a key modifier of the cellular response to endogenous dsRNA. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-12-21T21:22:18.613886-05:
      DOI: 10.1002/wrna.1322
  • Can circulating miRNAs live up to the promise of being minimal invasive
           biomarkers in clinical settings?
    • Authors: Andreas Keller; Eckart Meese
      Abstract: MicroRNAs have been discussed as non‐ or minimal invasive biomarkers with a remarkable extracellular stability. Despite a multitude of studies in basic research, there are only few independent validation studies on blood‐born miRNAs as disease markers. Toward clinical applications numerous obstacles still need to be overcome. They are of technical origin but also fundamentally associated with the source and the nature of miRNAs. Here, we emphasize on potential confounding factors, the nature and the source of miRNAs. We recently showed that age and gender could influence the pattern of circulating miRNAs. On the cellular level, the miRNA pattern differs between plasma and serum preparations. On the molecular level, one has to differentiate between extracellular miRNAs that are encapsulated in microvesicles or bound to proteins or high‐density lipoproteins. Using whole blood as source for miRNAs helps to minimize miRNA expression changes due to environmental influences and allows attributing miRNA changes to their cells of origin like B‐cells and T‐cells. Moreover, unambiguous annotation and differentiation from other noncoding RNAs can be challenging. Even not all miRNAs deposited in miRBase do necessarily represent true miRNAs, just a fraction of miRNAs in the reference database have been experimentally validated by Northern blotting. Functional evidence for a true miRNA should be obtained by cloning the precursor miRNA and by subsequent detection of the processed mature form in host cells. Surprisingly, attempts to finally confirm a true miRNA are frequently postponed until evidence has been established for a likely value as biomarker. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-12-15T21:46:18.474451-05:
      DOI: 10.1002/wrna.1320
  • lncRNAs regulate the innate immune response to viral infection
    • Abstract: Long noncoding RNAs (lncRNAs) are extensively expressed in mammalian cells and play a crucial role as RNA regulators in various cellular processes. Increasing data reveal that they function in innate antiviral immunity through complex mechanisms. Thousands of lncRNAs are regulated by RNA virus or DNA virus infection. The significant differential expression of lncRNAs is induced by virus or host antiviral signaling mediated by interferons (IFNs) and tumor necrosis factor‐α. In turn, these lncRNAs modulate the host immune response including the pathogen recognition receptor (PRR)‐related signaling, the translocation and activation of transcription factors, the production of IFNs and cytokines, the IFN‐activated JAK‐STAT signaling and the transcription of antiviral IFN‐stimulated genes (ISGs). Using gain‐ or loss‐of‐function analysis, the effect of lncRNAs on viral replication has been investigated to elucidate the essential role of lncRNA in the host–virus interaction. lncRNAs have shown specifically elevated or decreased levels in patients with viral diseases, suggesting the possibility of clinical application as biomarkers. Here we review the current advances of viral infection‐associated host lncRNAs, their functional significance in different aspects of antiviral immune response, the specific mechanisms and unsolved issues. We also summarize the regulation of lncRNAs by viruses, PRR agonists and cytokines. In addition, virus‐encoded lncRNAs and their functional involvement in host–virus interaction are addressed. For further resources related to this article, please visit the WIREs website.
      PubDate: 2015-12-15T04:25:23.054182-05:
      DOI: 10.1002/wrna.1321
  • 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
  • Issue information
    • Pages: 1 - 3
      PubDate: 2015-12-23T21:25:28.855175-05:
      DOI: 10.1002/wrna.1301
  • Satellite RNA pathogens of plants: impacts and origins—an RNA
           silencing perspective
    • First page: 5
      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
  • Prp40 and early events in splice site definition
    • First page: 17
      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
  • Trypanosome RNA editing: the complexity of getting U in and taking U out
    • First page: 33
      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
  • The sweet side of RNA regulation: glyceraldehyde‐3‐phosphate
           dehydrogenase as a noncanonical RNA‐binding protein
    • Authors: Michael R. White; Elsa D. Garcin
      First page: 53
      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
  • Roles for SUMO in pre‐mRNA processing
    • First page: 105
      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 Ccr4‐Not complex is a key regulator of eukaryotic gene
    • Abstract: The Ccr4‐Not complex is a multisubunit complex present in all eukaryotes that contributes to regulate gene expression at all steps, from production of messenger RNAs (mRNAs) in the nucleus to their degradation in the cytoplasm. In the nucleus it influences the post‐translational modifications of the chromatin template that has to be remodeled for transcription, it is present at sites of transcription and associates with transcription factors as well as with the elongating polymerase, it interacts with the factors that prepare the new transcript for export to the cytoplasm and finally is important for nuclear quality control and influences mRNA export. In the cytoplasm it is present in polysomes where mRNAs are translated and in RNA granules where mRNAs will be redirected upon inhibition of translation. It influences mRNA translatability, and is needed during translation, on one hand for co‐translational protein interactions and on the other hand to preserve translation that stalls. It is one of the relevant players during co‐translational quality control. It also interacts with factors that will repress translation or induce mRNA decapping when recruited to the translating template. Finally, Ccr4‐Not carries deadenylating enzymes and is a key player in mRNA decay, generic mRNA decay that follows normal translation termination, co‐translational mRNA decay of transcripts on which the ribosomes stall durably or which carry a non‐sense mutation and finally mRNA decay that is induced by external signaling for a change in genetic programming. Ccr4‐Not is a master regulator of eukaryotic gene expression. For further resources related to this article, please visit the WIREs website.
  • RNA‐binding protein hnRNPLL as a critical regulator of lymphocyte
           homeostasis and differentiation
    • Abstract: RNA‐binding proteins orchestrate posttranscriptional regulation of gene expression, such as messenger RNA (mRNA) splicing, RNA stability regulation, and translation regulation. Heterogeneous nuclear RNA‐binding proteins (hnRNPs) refer to a collection of unrelated RNA‐binding proteins predominantly located in the nucleus (Han et al. Biochem J 2010, 430:379–392). Although canonical functions of hnRNPs are to promote pre‐mRNA splicing, they are involved in all the processes of RNA metabolism through recognizing specific cis‐elements on RNA (Dreyfuss et al. Annu Rev Biochem 1993, 62:289–321; Huelga et al. Cell Rep 2012, 1:167–178; Krecic and Swanson. Curr Opin Cell Biol 1999, 11:363–371). Heterogeneous nuclear RNA‐binding protein L like (hnRNPLL) is a tissue‐specific hnRNP, which was identified as a regulator of CD45RA to CD45RO switching during memory T‐cell development (Oberdoerffer et al. Science 2008, 321:686–691; Topp et al. RNA 2008, 14:2038–2049; Wu et al. Immunity 2008, 29:863–875). Since then, hnRNPLL has emerged as a critical regulator of lymphocyte homeostasis and terminal differentiation, controlling alternative splicing or expression of critical genes for the lymphocytes development (Wu et al. Immunity 2008, 29:863–875; Chang et al. Proc Natl Acad Sci USA 2015, 112:E1888–E1897). This review will summarize recent advances in understanding the functions of hnRNPLL, focusing on its biochemical functions and physiological roles in lymphocyte differentiation and homeostasis. For further resources related to this article, please visit the WIREs website.
  • FUS‐mediated regulation of alternative RNA processing in neurons:
           insights from global transcriptome analysis
    • Abstract: Fused in sarcoma (FUS) is an RNA‐binding protein that is causally associated with oncogenesis and neurodegeneration. Recently, the role of FUS in neurodegeneration has been extensively studied, because mutations in FUS are associated with amyotrophic lateral sclerosis (ALS), and the FUS protein has been identified as a major component of intracellular inclusions in neurodegenerative disorders including ALS and frontotemporal lobar degeneration. FUS is a key molecule in transcriptional regulation and RNA processing including processes such as pre‐messenger RNA (mRNA) splicing and polyadenylation. Interaction of FUS with various components of the transcription machinery, spliceosome, and the 3′‐end processing machinery has been identified. Furthermore, recent advances in high‐throughput transcriptomic profiling approaches have enabled us to determine the mechanisms of FUS‐dependent RNA processing networks at a cellular level. These analyses have revealed that depletion of FUS in neuronal cells affects alternative splicing and alternative polyadenylation of thousands of mRNAs. Gene ontology analysis has suggested that FUS‐modulated genes are implicated in neuronal functions and development. CLIP‐seq of FUS has shown that FUS is frequently clustered around these alternative sites of nascent RNA. ChIP‐seq of RNA polymerase II (RNAP II) has demonstrated that an interaction between FUS and nascent RNA downregulates local transcriptional activity of RNAP II, which is critically involved in RNA processing. Both alternative splicing and alternative polyadenylation are fundamental processes by which cells expand their transcriptomic diversity, and are particularly essential in the nervous system. Dependence of transcriptomic diversity on FUS makes the nervous system vulnerable to neurodegeneration, when FUS is functionally compromised. For further resources related to this article, please visit the WIREs website.
  • Matrin3: connecting gene expression with the nuclear matrix
    • Abstract: As indicated by its name, Matrin3 was discovered as a component of the nuclear matrix, an insoluble fibrogranular network that structurally organizes the nucleus. Matrin3 possesses both DNA‐ and RNA‐binding domains and, consistent with this, has been shown to function at a number of stages in the life cycle of messenger RNAs. These numerous activities indicate that Matrin3, and indeed the nuclear matrix, do not just provide a structural framework for nuclear activities but also play direct functional roles in these activities. Here, we review the structure, functions, and molecular interactions of Matrin3 and of Matrin3‐related proteins, and the pathologies that can arise upon mutation of Matrin3. For further resources related to this article, please visit the WIREs website.
  • Prohead RNA: a noncoding viral RNA of novel structure and function
    • Abstract: Prohead RNA (pRNA) is an essential component of the powerful Φ29‐like bacteriophage DNA packaging motor. However, the specific role of this unique RNA in the Φ29 packaging motor remains unknown. This review examines pRNA as a noncoding RNA of novel structure and function. In order to highlight the reasons for exploring the structure and function of pRNA, we (1) provide an overview of Φ29‐like bacteriophage and the Φ29 DNA packaging motor, including putative motor mechanisms and structures of its component parts; (2) discuss pRNA structure and possible roles for pRNA in the Φ29 packaging motor; (3) summarize pRNA self‐assembly; and (4) describe the prospective therapeutic applications of pRNA. Many questions remain to be answered in order to connect what is currently known about pRNA structure to its novel function in the Φ29 packaging motor. The knowledge gained from studying the structure, function, and sequence variation in pRNA will help develop tools to better navigate the conformational landscapes of RNA. For further resources related to this article, please visit the WIREs website.
  • The KSHV RNA regulator ORF57: target specificity and its role in the viral
           life cycle
    • Abstract: Kaposi's sarcoma‐associated herpesvirus (KSHV) encodes ORF57, which enhances the expression of intron‐less KSHV genes on multiple post‐transcriptional levels mainly affecting RNA stability and export to the cytoplasm. Yet, it remains elusive how ORF57 recognizes viral RNAs and discriminates them from cellular messenger RNAs (mRNAs). Although one common binding motif on three separate KSHV RNAs has been described, most other lytic genes lack this sequence element. In this article we will review the sequence requirements for ORF57 to enhance RNA expression and discuss a model how ORF57 achieves specificity for viral RNAs. Finally, the role of ORF57 is integrated into the viral life cycle as a complex interplay with other viral and host factors and with implications for cellular gene expression. For further resources related to this article, please visit the WIREs website.
  • Bioengineering of noncoding RNAs for research agents and therapeutics
    • Abstract: The discovery of functional small noncoding RNAs (ncRNAs), such as microRNAs and small interfering RNAs, in the control of human cellular processes has opened new avenues to develop RNA‐based therapies for various diseases including viral infections and cancers. However, studying ncRNA functions and developing RNA‐based therapeutics relies on access to large quantities of affordable ncRNA agents. Currently, synthetic RNAs account for the major source of agents for RNA research and development, yet carry artificial modifications on the ribose ring and phosphate backbone in sharp contrast to posttranscriptional modifications present on the nucleobases or unmodified natural RNA molecules produced within cells. Therefore, large efforts have been made in recent years to develop recombinant RNA techniques to cost‐effectively produce biological RNA agents that may better capture the structure, function, and safety properties of natural RNAs. In this article, we summarize and compare current in vitro and in vivo methods for the production of RNA agents including chemical synthesis, in vitro transcription, and bioengineering approaches. We highlight the latest recombinant RNA approaches using transfer RNA (tRNA), ribosomal RNA (rRNA), and optimal ncRNA scaffold (OnRS), and discuss the applications of bioengineered ncRNA agents (BERAs) that should facilitate RNA research and development. For further resources related to this article, please visit the WIREs website.
  • Nucleocapsid proteins: roles beyond viral RNA packaging
    • Abstract: Viral nucleocapsid proteins (NCs) enwrap the RNA genomes of viruses to form NC–RNA complexes, which act as a template and are essential for viral replication and transcription. Beyond packaging viral RNA, NCs also play important roles in virus replication, transcription, assembly, and budding by interacting with viral and host cellular proteins. Additionally, NCs can inhibit interferon signaling response and function in cell stress response, such as inducing apoptosis. Finally, NCs can be the target of vaccines, benefiting from their conserved gene sequences. Here, we summarize important findings regarding the additional functions of NCs as much more than structural RNA‐binding proteins, with specific emphasis on (1) their association with the viral life cycle, (2) their association with host cells, and (3) as ideal candidates for vaccine development. For further resources related to this article, please visit the WIREs website.
  • Regulation and functions of bacterial PNPase
    • Abstract: Polynucleotide phosphorylase (PNPase) is an exoribonuclease that catalyzes the processive phosphorolytic degradation of RNA from the 3′‐end. The enzyme catalyzes also the reverse reaction of polymerization of nucleoside diphosphates that has been implicated in the generation of heteropolymeric tails at the RNA 3′‐end. The enzyme is widely conserved and plays a major role in RNA decay in both Gram‐negative and Gram‐positive bacteria. Moreover, it participates in maturation and quality control of stable RNA. PNPase autoregulates its own expression at post‐transcriptional level through a complex mechanism that involves the endoribonuclease RNase III and translation control. The activity of PNPase is modulated in an intricate and still unclear manner by interactions with small molecules and recruitment in different multiprotein complexes. Not surprisingly, given the wide spectrum of PNPase substrates, PNPase‐defective mutations in different bacterial species have pleiotropic effects and perturb the execution of genetic programs involving drastic changes in global gene expression such as biofilm formation, growth at suboptimal temperatures, and virulence. For further resources related to this article, please visit the WIREs website.
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