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Results: 1 to 10 of 26

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Quelling an innate response to dsRNA.
Ogden KM, Prasad BV
(2015) Oncotarget 6: 28535-6
MeSH Terms: 2',5'-Oligoadenylate Synthetase, Animals, Antiviral Agents, Endoribonucleases, Evolution, Molecular, Exoribonucleases, Gene Expression Regulation, Viral, Host-Pathogen Interactions, Humans, Immunity, Innate, Molecular Targeted Therapy, Nucleic Acid Conformation, Phosphodiesterase Inhibitors, RNA, Double-Stranded, RNA, Viral, Signal Transduction, Viral Proteins, Viruses
Added April 26, 2017
0 Communities
1 Members
0 Resources
18 MeSH Terms
Structural and functional insights into the N-terminus of Schizosaccharomyces pombe Cdc5.
Collier SE, Voehler M, Peng D, Ohi R, Gould KL, Reiter NJ, Ohi MD
(2014) Biochemistry 53: 6439-51
MeSH Terms: Binding Sites, Catalytic Domain, Cell Cycle Proteins, Gene Deletion, Models, Molecular, Mutant Proteins, Nuclear Magnetic Resonance, Biomolecular, Peptide Fragments, Protein Conformation, Protein Folding, Protein Interaction Domains and Motifs, Protein Stability, RNA Splicing, RNA, Double-Stranded, RNA, Fungal, RNA, Small Nuclear, RNA-Binding Proteins, Recombinant Proteins, Schizosaccharomyces pombe Proteins, Spliceosomes, Titrimetry
Show Abstract · Added January 20, 2015
The spliceosome is a dynamic macromolecular machine composed of five small nuclear ribonucleoparticles (snRNPs), the NineTeen Complex (NTC), and other proteins that catalyze the removal of introns mature to form the mature message. The NTC, named after its founding member Saccharomyces cerevisiae Prp19, is a conserved spliceosome subcomplex composed of at least nine proteins. During spliceosome assembly, the transition to an active spliceosome correlates with stable binding of the NTC, although the mechanism of NTC function is not understood. Schizosaccharomyces pombe Cdc5, a core subunit of the NTC, is an essential protein required for pre-mRNA splicing. The highly conserved Cdc5 N-terminus contains two canonical Myb (myeloblastosis) repeats (R1 and R2) and a third domain (D3) that was previously classified as a Myb-like repeat. Although the N-terminus of Cdc5 is required for its function, how R1, R2, and D3 each contribute to functionality is unclear. Using a combination of yeast genetics, structural approaches, and RNA binding assays, we show that R1, R2, and D3 are all required for the function of Cdc5 in cells. We also show that the N-terminus of Cdc5 binds RNA in vitro. Structural and functional analyses of Cdc5-D3 show that, while this domain does not adopt a Myb fold, Cdc5-D3 preferentially binds double-stranded RNA. Our data suggest that the Cdc5 N-terminus interacts with RNA structures proposed to be near the catalytic core of the spliceosome.
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4 Members
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21 MeSH Terms
RNAi-mediated gene silencing in zebrafish triggered by convergent transcription.
Andrews OE, Cha DJ, Wei C, Patton JG
(2014) Sci Rep 4: 5222
MeSH Terms: Animals, Gene Expression, Gene Silencing, Heterochromatin, Promoter Regions, Genetic, RNA Interference, RNA, Double-Stranded, Transcription, Genetic, Transgenes, Zebrafish
Show Abstract · Added January 20, 2015
RNAi based strategies to induce gene silencing are commonly employed in numerous model organisms but have not been extensively used in zebrafish. We found that introduction of transgenes containing convergent transcription units in zebrafish embryos induced stable transcriptional gene silencing (TGS) in cis and trans for reporter (mCherry) and endogenous (One-Eyed Pinhead (OEP) and miR-27a/b) genes. Convergent transcription enabled detection of both sense and antisense transcripts and silencing was suppressed upon Dicer knockdown, indicating processing of double stranded RNA. By ChIP analyses, increased silencing was accompanied by enrichment of the heterochromatin mark H3K9me3 in the two convergently arranged promoters and in the intervening reading frame. Our work demonstrates that convergent transcription can induce gene silencing in zebrafish providing another tool to create specific temporal and spatial control of gene expression.
0 Communities
1 Members
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10 MeSH Terms
Reovirus replication protein μ2 influences cell tropism by promoting particle assembly within viral inclusions.
Ooms LS, Jerome WG, Dermody TS, Chappell JD
(2012) J Virol 86: 10979-87
MeSH Terms: Animals, Cell Line, Dogs, Inclusion Bodies, Viral, Madin Darby Canine Kidney Cells, Mice, Microscopy, Electron, Transmission, Phenotype, RNA, Double-Stranded, RNA, Viral, Reoviridae, Temperature, Viral Nonstructural Proteins, Viral Proteins, Viral Tropism, Virus Assembly, Virus Replication
Show Abstract · Added December 10, 2013
The double-stranded RNA virus mammalian reovirus displays broad cell, tissue, and host tropism. A critical checkpoint in the reovirus replication cycle resides within viral cytoplasmic inclusions, which are biosynthetic centers of genome multiplication and new-particle assembly. Replication of strain type 3 Dearing (T3) is arrested in Madin-Darby canine kidney (MDCK) cells at a step subsequent to inclusion development and prior to formation of genomic double-stranded RNA. This phenotype is primarily regulated by viral replication protein μ2. To understand how reovirus inclusions differ in productively and abortively infected MDCK cells, we used confocal immunofluorescence and thin-section transmission electron microscopy (TEM) to probe inclusion organization and particle morphogenesis. Although no abnormalities in inclusion morphology or viral protein localization were observed in T3-infected MDCK cells using confocal microscopy, TEM revealed markedly diminished production of mature progeny virions. T3 inclusions were less frequent and smaller than those formed by T3-T1M1, a productively replicating reovirus strain, and contained decreased numbers of complete particles. T3 replication was enhanced when cells were cultivated at 31°C, and inclusion ultrastructure at low-temperature infection more closely resembled that of a productive infection. These results indicate that particle assembly in T3-infected MDCK cells is defective, possibly due to a temperature-sensitive structural or functional property of μ2. Thus, reovirus cell tropism can be governed by interactions between viral replication proteins and the unique cell environment that modulate efficiency of particle assembly.
1 Communities
2 Members
0 Resources
17 MeSH Terms
Unexpected origins of the enhanced pairing affinity of 2'-fluoro-modified RNA.
Pallan PS, Greene EM, Jicman PA, Pandey RK, Manoharan M, Rozners E, Egli M
(2011) Nucleic Acids Res 39: 3482-95
MeSH Terms: Crystallography, X-Ray, Fluorine, Models, Molecular, Nucleic Acid Conformation, Osmotic Pressure, RNA Stability, RNA, Double-Stranded, Thermodynamics, Water
Show Abstract · Added March 7, 2014
Various chemical modifications are currently being evaluated for improving the efficacy of short interfering RNA (siRNA) duplexes as antisense agents for gene silencing in vivo. Among the 2'-ribose modifications assessed to date, 2'deoxy-2'-fluoro-RNA (2'-F-RNA) has unique properties for RNA interference (RNAi) applications. Thus, 2'-F-modified nucleotides are well tolerated in the guide (antisense) and passenger (sense) siRNA strands and the corresponding duplexes lack immunostimulatory effects, enhance nuclease resistance and display improved efficacy in vitro and in vivo compared with unmodified siRNAs. To identify potential origins of the distinct behaviors of RNA and 2'-F-RNA we carried out thermodynamic and X-ray crystallographic analyses of fully and partially 2'-F-modified RNAs. Surprisingly, we found that the increased pairing affinity of 2'-F-RNA relative to RNA is not, as commonly assumed, the result of a favorable entropic contribution ('conformational preorganization'), but instead primarily based on enthalpy. Crystal structures at high resolution and osmotic stress demonstrate that the 2'-F-RNA duplex is less hydrated than the RNA duplex. The enthalpy-driven, higher stability of the former hints at the possibility that the 2'-substituent, in addition to its important function in sculpting RNA conformation, plays an underappreciated role in modulating Watson-Crick base pairing strength and potentially π-π stacking interactions.
0 Communities
1 Members
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9 MeSH Terms
Residues of the rotavirus RNA-dependent RNA polymerase template entry tunnel that mediate RNA recognition and genome replication.
Ogden KM, Ramanathan HN, Patton JT
(2011) J Virol 85: 1958-69
MeSH Terms: Amino Acid Sequence, Animals, Cell Line, DNA Replication, Genome, Viral, Models, Molecular, Molecular Sequence Data, RNA Replicase, RNA, Double-Stranded, RNA, Viral, Rotavirus, Templates, Genetic, Viral Proteins, Virus Replication
Show Abstract · Added April 26, 2017
To replicate its segmented, double-stranded RNA (dsRNA) genome, the rotavirus RNA-dependent RNA polymerase, VP1, must recognize viral plus-strand RNAs (+RNAs) and guide them into the catalytic center. VP1 binds to the conserved 3' end of rotavirus +RNAs via both sequence-dependent and sequence-independent contacts. Sequence-dependent contacts permit recognition of viral +RNAs and specify an autoinhibited positioning of the template within the catalytic site. However, the contributions to dsRNA synthesis of sequence-dependent and sequence-independent VP1-RNA interactions remain unclear. To analyze the importance of VP1 residues that interact with +RNA on genome replication, we engineered mutant VP1 proteins and assayed their capacity to synthesize dsRNA in vitro. Our results showed that, individually, mutation of residues that interact specifically with RNA bases did not diminish replication levels. However, simultaneous mutations led to significantly lower levels of dsRNA product, presumably due to impaired recruitment of +RNA templates. In contrast, point mutations of sequence-independent RNA contact residues led to severely diminished replication, likely as a result of improper positioning of templates at the catalytic site. A noteworthy exception was a K419A mutation that enhanced the initiation capacity and product elongation rate of VP1. The specific chemistry of Lys419 and its position at a narrow region of the template entry tunnel appear to contribute to its capacity to moderate replication. Together, our findings suggest that distinct classes of VP1 residues interact with +RNA to mediate template recognition and dsRNA synthesis yet function in concert to promote viral RNA replication at appropriate times and rates.
0 Communities
1 Members
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14 MeSH Terms
A post-entry step in the mammalian orthoreovirus replication cycle is a determinant of cell tropism.
Ooms LS, Kobayashi T, Dermody TS, Chappell JD
(2010) J Biol Chem 285: 41604-13
MeSH Terms: Animals, Cell Line, Chick Embryo, DNA-Directed RNA Polymerases, Dogs, Models, Genetic, Molecular Sequence Data, Mutation, RNA, Double-Stranded, RNA, Viral, Reoviridae, Reverse Transcriptase Polymerase Chain Reaction, Viral Tropism, Virus Replication
Show Abstract · Added December 10, 2013
Mammalian reoviruses replicate in a broad range of hosts, cells, and tissues. These viruses display strain-dependent variation in tropism for different types of cells in vivo and ex vivo. Early steps in the reovirus life cycle, attachment, entry, and disassembly, have been identified as pivotal points of virus-cell interaction that determine the fate of infection, either productive or abortive. However, in studies of the differential capacity of reovirus strains type 1 Lang and type 3 Dearing to replicate in Madin-Darby canine kidney (MDCK) cells, we found that replication efficiency is regulated at a late point in the viral life cycle following primary transcription and translation. Results of genetic studies using recombinant virus strains show that reovirus tropism for MDCK cells is primarily regulated by replication protein μ2 and further influenced by the viral RNA-dependent RNA polymerase protein, λ3, depending on the viral genetic background. Furthermore, μ2 residue 347 is a critical determinant of replication efficiency in MDCK cells. These findings indicate that components of the reovirus replication complex are mediators of cell-selective viral replication capacity at a post-entry step. Thus, reovirus cell tropism may be determined at early and late points in the viral replication program.
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1 Members
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14 MeSH Terms
The solution structure of the ADAR2 dsRBM-RNA complex reveals a sequence-specific readout of the minor groove.
Stefl R, Oberstrass FC, Hood JL, Jourdan M, Zimmermann M, Skrisovska L, Maris C, Peng L, Hofr C, Emeson RB, Allain FH
(2010) Cell 143: 225-37
MeSH Terms: Adenosine Deaminase, Amino Acid Sequence, Animals, Cell Line, Humans, Mice, Models, Molecular, Molecular Sequence Data, Mutation, Nuclear Magnetic Resonance, Biomolecular, RNA Precursors, RNA, Double-Stranded, RNA-Binding Proteins, Rats, Receptors, AMPA, Sequence Alignment
Show Abstract · Added May 28, 2014
Sequence-dependent recognition of dsDNA-binding proteins is well understood, yet sequence-specific recognition of dsRNA by proteins remains largely unknown, despite their importance in RNA maturation pathways. Adenosine deaminases that act on RNA (ADARs) recode genomic information by the site-selective deamination of adenosine. Here, we report the solution structure of the ADAR2 double-stranded RNA-binding motifs (dsRBMs) bound to a stem-loop pre-mRNA encoding the R/G editing site of GluR-2. The structure provides a molecular basis for how dsRBMs recognize the shape, and also more surprisingly, the sequence of the dsRNA. The unexpected direct readout of the RNA primary sequence by dsRBMs is achieved via the minor groove of the dsRNA and this recognition is critical for both editing and binding affinity at the R/G site of GluR-2. More generally, our findings suggest a solution to the sequence-specific paradox faced by many dsRBM-containing proteins that are involved in post-transcriptional regulation of gene expression.
Copyright © 2010 Elsevier Inc. All rights reserved.
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1 Members
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16 MeSH Terms
Contributions of functional genomics and proteomics to the study of immune responses in the Pacific white leg shrimp Litopenaeus vannamei.
Robalino J, Carnegie RB, O'Leary N, Ouvry-Patat SA, de la Vega E, Prior S, Gross PS, Browdy CL, Chapman RW, Schey KL, Warr G
(2009) Vet Immunol Immunopathol 128: 110-8
MeSH Terms: Animals, Gene Expression Regulation, Genetic Variation, Genomics, Oligonucleotide Array Sequence Analysis, Penaeidae, Proteomics, RNA Interference, RNA, Double-Stranded
Show Abstract · Added May 27, 2014
The need for better control of infectious diseases in shrimp aquaculture and the ecological importance of crustacea in marine ecosystems have prompted interest in the study of crustacean immune systems, particularly those of shrimp. As shrimp and other crustacea are poorly understood from the immunological point of view, functional genomic and proteomic approaches have been applied as a means of quickly obtaining molecular information regarding immune responses in these organisms. In this article, a series of results derived from transcriptomic and proteomic studies in shrimp (Litopenaeus vannamei) are discussed. Expressed Sequence Tag analysis, differential expression cloning through Suppression Subtractive Hybridization, expression profiling using microarrays, and proteomic studies using mass spectrometry, have provided a wealth of useful data and opportunities for new avenues of research. Examples of new research directions arising from these studies in shrimp include the molecular diversity of antimicrobial effectors, the role of double stranded RNA as an inducer of antiviral immunity, and the possible overlap between antibacterial and antiviral responses in the shrimp.
0 Communities
1 Members
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9 MeSH Terms
Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5.
Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S
(2008) J Exp Med 205: 1601-10
MeSH Terms: Animals, Cell Line, DEAD Box Protein 58, DEAD-box RNA Helicases, Interferon-Induced Helicase, IFIH1, Mice, RNA, Double-Stranded, RNA, Viral, Vesicular Stomatitis, Vesiculovirus
Show Abstract · Added December 10, 2013
The ribonucleic acid (RNA) helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) recognize distinct viral and synthetic RNAs, leading to the production of interferons. Although 5'-triphosphate single-stranded RNA is a RIG-I ligand, the role of RIG-I and MDA5 in double-stranded (ds) RNA recognition remains to be characterized. In this study, we show that the length of dsRNA is important for differential recognition by RIG-I and MDA5. The MDA5 ligand, polyinosinic-polycytidylic acid, was converted to a RIG-I ligand after shortening of the dsRNA length. In addition, viral dsRNAs differentially activated RIG-I and MDA5, depending on their length. Vesicular stomatitis virus infection generated dsRNA, which is responsible for RIG-I-mediated recognition. Collectively, RIG-I detects dsRNAs without a 5'-triphosphate end, and RIG-I and MDA5 selectively recognize short and long dsRNAs, respectively.
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1 Members
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10 MeSH Terms