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[PMID]:29028835
[Au] Autor:Mullen NJ; Price DH
[Ad] Endereço:Department of Biochemistry, University of Iowa, Iowa City, Iowa, United States of America.
[Ti] Título:Hydrogen peroxide yields mechanistic insights into human mRNA capping enzyme function.
[So] Source:PLoS One;12(10):e0186423, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Capping of nascent RNA polymerase II (Pol II) transcripts is required for gene expression and the first two steps are catalyzed by separate 5' triphosphatase and guanylyltransferase activities of the human capping enzyme (HCE). The cap is added co-transcriptionally, but how the two activities are coordinated is unclear. Our previous in vitro work has suggested that an unidentified factor modulates the minimum length at which nascent transcripts can be capped. Using the same well-established in vitro system with hydrogen peroxide as a capping inhibitor, we show that this unidentified factor targets the guanylyltransferase activity of HCE. We also uncover the mechanism of HCE inhibition by hydrogen peroxide, and by using mass spectrometry demonstrate that the active site cysteine residue of the HCE triphosphatase domain becomes oxidized. Using recombinant proteins for the two separated HCE domains, we provide evidence that the triphosphatase normally acts on transcripts shorter than can be acted upon by the guanylyltransferase. Our further characterization of the capping reaction dependence on transcript length and its interaction with the unidentified modulator of capping raises the interesting possibility that the capping reaction could be regulated.
[Mh] Termos MeSH primário: Peróxido de Hidrogênio/farmacologia
Nucleosídeo-Trifosfatase/metabolismo
Nucleotidiltransferases/metabolismo
Capuzes de RNA/metabolismo
[Mh] Termos MeSH secundário: Sequência de Bases
Biocatálise
Inibidores Enzimáticos/farmacologia
Seres Humanos
Modelos Moleculares
Nucleosídeo-Trifosfatase/antagonistas & inibidores
Nucleosídeo-Trifosfatase/química
Nucleotidiltransferases/antagonistas & inibidores
Nucleotidiltransferases/química
Domínios Proteicos
Capuzes de RNA/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (RNA Caps); BBX060AN9V (Hydrogen Peroxide); EC 2.7.7.- (Nucleotidyltransferases); EC 2.7.7.- (guanylyltransferase); EC 3.6.1.15 (Nucleoside-Triphosphatase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171014
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186423


  2 / 2265 MEDLINE  
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[PMID]:28981715
[Au] Autor:Trotman JB; Giltmier AJ; Mukherjee C; Schoenberg DR
[Ad] Endereço:Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA.
[Ti] Título:RNA guanine-7 methyltransferase catalyzes the methylation of cytoplasmically recapped RNAs.
[So] Source:Nucleic Acids Res;45(18):10726-10739, 2017 Oct 13.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cap homeostasis is a cyclical process of decapping and recapping that impacts a portion of the mRNA transcriptome. The metastable uncapped forms of recapping targets redistribute from polysomes to non-translating mRNPs, and recapping is all that is needed for their return to the translating pool. Previous work identified a cytoplasmic capping metabolon consisting of capping enzyme (CE) and a 5'-monophosphate kinase bound to adjacent domains of Nck1. The current study identifies the canonical cap methyltransferase (RNMT) as the enzyme responsible for guanine-N7 methylation of recapped mRNAs. RNMT binds directly to CE, and its presence in the cytoplasmic capping complex was demonstrated by pulldown assays, gel filtration and proximity-dependent biotinylation. The latter also identified the RNMT cofactor RAM, whose presence is required for cytoplasmic cap methyltransferase activity. These findings guided development of an inhibitor of cytoplasmic cap methylation whose action resulted in a selective decrease in levels of recapped mRNAs.
[Mh] Termos MeSH primário: Citoplasma/enzimologia
Metiltransferases/metabolismo
Capuzes de RNA/metabolismo
Proteínas de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Biocatálise
Linhagem Celular Tumoral
Núcleo Celular/enzimologia
Células HEK293
Seres Humanos
Metilação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA Caps); 0 (RNA-Binding Proteins); EC 2.1.1.- (Fam103a1 protein, human); EC 2.1.1.- (Methyltransferases); EC 2.1.1.56 (mRNA (guanine(N7))-methyltransferase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171006
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx801


  3 / 2265 MEDLINE  
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[PMID]:28934492
[Au] Autor:Du Z; Alekhina OM; Vassilenko KS; Simon AE
[Ad] Endereço:Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
[Ti] Título:Concerted action of two 3' cap-independent translation enhancers increases the competitive strength of translated viral genomes.
[So] Source:Nucleic Acids Res;45(16):9558-9572, 2017 Sep 19.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Several families of plant viruses evolved cap-independent translation enhancers (3'CITE) in the 3' untranslated regions of their genomic (g)RNAs to compete with ongoing cap-dependent translation of cellular mRNAs. Umbravirus Pea enation mosaic virus (PEMV)2 is the only example where three 3'CITEs enhance translation: the eIF4E-binding Panicum mosaic virus-like translational enhancer (PTE) and ribosome-binding 3' T-shaped structure (TSS) have been found in viruses of different genera, while the ribosome-binding kl-TSS that provides a long-distance interaction with the 5' end is unique. We report that the PTE is the key translation promoting element, but inhibits translation in cis and in trans in the absence of the kl-TSS by sequestering initiation factor eIF4G. PEMV2 strongly outcompeted a cellular mRNA mimic for translation, indicating that the combination of kl-TSS and PTE is highly efficient. Transferring the 3'-5' interaction from the kl-TSS to the PTE (to fulfill its functionality as found in other viruses) supported translationin vitro, but gRNA did not accumulate to detectable levels in protoplasts in the absence of the kl-TSS. It was shown that the PTE in conjunction with the kl-TSS did not markedly affect the translation initiation rate but rather increased the number of gRNAs available for translation. A model is proposed to explain how 3'CITE-based regulation of ribosome recruitment enhances virus fitness.
[Mh] Termos MeSH primário: Elementos Facilitadores Genéticos
Genoma Viral
Luteoviridae/genética
Capuzes de RNA/genética
[Mh] Termos MeSH secundário: Arabidopsis/virologia
Códon de Iniciação
Fator de Iniciação 4G em Eucariotos/genética
Fator de Iniciação 4G em Eucariotos/metabolismo
Luteoviridae/metabolismo
Polirribossomos/metabolismo
Biossíntese de Proteínas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Codon, Initiator); 0 (Eukaryotic Initiation Factor-4G); 0 (RNA Caps)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx643


  4 / 2265 MEDLINE  
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[PMID]:28854224
[Au] Autor:Dhungel P; Cao S; Yang Z
[Ad] Endereço:Division of Biology, Kansas State University, Manhattan, Kansas, United States of America.
[Ti] Título:The 5'-poly(A) leader of poxvirus mRNA confers a translational advantage that can be achieved in cells with impaired cap-dependent translation.
[So] Source:PLoS Pathog;13(8):e1006602, 2017 Aug.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The poly(A) leader at the 5'-untranslated region (5'-UTR) is an unusually striking feature of all poxvirus mRNAs transcribed after viral DNA replication (post-replicative mRNAs). These poly(A) leaders are non-templated and of heterogeneous lengths; and their function during poxvirus infection remains a long-standing question. Here, we discovered that a 5'-poly(A) leader conferred a selective translational advantage to mRNA in poxvirus-infected cells. A constitutive and uninterrupted 5'-poly(A) leader with 12 residues was optimal. Because the most frequent lengths of the 5'-poly(A) leaders are 8-12 residues, the result suggests that the poly(A) leader has been evolutionarily optimized to boost poxvirus protein production. A 5'-poly(A) leader also could increase protein production in the bacteriophage T7 promoter-based expression system of vaccinia virus, the prototypic member of poxviruses. Interestingly, although vaccinia virus post-replicative mRNAs do have 5'- methylated guanosine caps and can use cap-dependent translation, in vaccinia virus-infected cells, mRNA with a 5'-poly(A) leader could also be efficiently translated in cells with impaired cap-dependent translation. However, the translation was not mediated through an internal ribosome entry site (IRES). These results point to a fundamental mechanism poxvirus uses to efficiently translate its post-replicative mRNAs.
[Mh] Termos MeSH primário: Biossíntese de Proteínas/genética
RNA Mensageiro/genética
RNA Viral/genética
Vírus Vaccinia/genética
Replicação Viral/genética
[Mh] Termos MeSH secundário: Regiões 5' não Traduzidas/genética
Western Blotting
Linhagem Celular
Técnicas de Silenciamento de Genes
Seres Humanos
Reação em Cadeia da Polimerase
Infecções por Poxviridae/genética
Capuzes de RNA/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5' Untranslated Regions); 0 (RNA Caps); 0 (RNA, Messenger); 0 (RNA, Viral)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170831
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006602


  5 / 2265 MEDLINE  
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[PMID]:28839112
[Au] Autor:Kamel W; Akusjärvi G
[Ad] Endereço:Department of Medical Biochemistry and Microbiology, BMC, Uppsala University, SE-751 23 Uppsala, Sweden.
[Ti] Título:An Ago2-associated capped transcriptional start site small RNA suppresses adenovirus DNA replication.
[So] Source:RNA;23(11):1700-1711, 2017 Nov.
[Is] ISSN:1469-9001
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Here we show that the adenovirus major late promoter produces a 31-nucleotide transcriptional start site small RNA (MLP-TSS-sRNA) that retains the 7-methylguanosine (m7G)-cap and is incorporated onto Ago2-containing RNA-induced silencing complexes (RISC) in human adenovirus-37 infected cells. RNA polymerase II CLIP (UV-cross linking immunoprecipitation) experiments suggest that the MLP-TSS-sRNA is produced by promoter proximal stalling/termination of RNA polymerase II transcription at the site of the small RNA 3' end. The MLP-TSS-sRNA is highly stable in cells and functionally active, down-regulating complementary targets in a sequence and dose-dependent manner. The MLP-TSS-sRNA is transcribed from the opposite strand to the adenoviral DNA polymerase and preterminal protein mRNAs, two essential viral replication proteins. We show that the MLP-TSS-sRNA act in to reduce DNA polymerase and preterminal protein mRNA expression. As a consequence of this, the MLP-TSS-sRNA has an inhibitory effect on the efficiency of viral DNA replication. Collectively, our results suggest that this novel sRNA may serve a regulatory function controlling viral genome replication during a lytic and/or persistent adenovirus infection in its natural host.
[Mh] Termos MeSH primário: Adenovírus Humanos/genética
Adenovírus Humanos/metabolismo
Proteínas Argonauta/metabolismo
Replicação do DNA/genética
RNA Viral/genética
RNA Viral/metabolismo
Replicação Viral/genética
[Mh] Termos MeSH secundário: Proteínas Argonauta/genética
Linhagem Celular
Genes Virais
Células HEK293
Células HeLa
Seres Humanos
Conformação de Ácido Nucleico
Regiões Promotoras Genéticas
Capuzes de RNA/química
Capuzes de RNA/genética
Capuzes de RNA/metabolismo
Estabilidade de RNA
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
RNA Viral/química
Complexo de Inativação Induzido por RNA/genética
Complexo de Inativação Induzido por RNA/metabolismo
Sítio de Iniciação de Transcrição
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Argonaute Proteins); 0 (EIF2C2 protein, human); 0 (RNA Caps); 0 (RNA, Messenger); 0 (RNA, Viral); 0 (RNA-Induced Silencing Complex)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170826
[St] Status:MEDLINE
[do] DOI:10.1261/rna.061291.117


  6 / 2265 MEDLINE  
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[PMID]:28821580
[Au] Autor:Marques-Ramos A; Candeias MM; Menezes J; Lacerda R; Willcocks M; Teixeira A; Locker N; Romão L
[Ad] Endereço:Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal.
[Ti] Título:Cap-independent translation ensures mTOR expression and function upon protein synthesis inhibition.
[So] Source:RNA;23(11):1712-1728, 2017 Nov.
[Is] ISSN:1469-9001
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The mechanistic/mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that integrates cellular signals from the nutrient and energy status to act, namely, on the protein synthesis machinery. While major advances have emerged regarding the regulators and effects of the mTOR signaling pathway, little is known about the regulation of gene expression. Here, we show that the human transcript can be translated in a cap-independent manner, and that its 5' untranslated region (UTR) is a highly folded RNA scaffold capable of binding directly to the 40S ribosomal subunit. We further demonstrate that is able to bypass the cap requirement for translation both in normal and hypoxic conditions. Moreover, our data reveal that the cap-independent translation of mTOR is necessary for its ability to induce cell-cycle progression into S phase. These results suggest a novel regulatory mechanism for gene expression that integrates the global protein synthesis changes induced by translational inhibitory conditions.
[Mh] Termos MeSH primário: Serina-Treonina Quinases TOR/genética
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Regiões 5' não Traduzidas
Animais
Hipóxia Celular/genética
Linhagem Celular
Evolução Molecular
Regulação da Expressão Gênica
Células HCT116
Células HEK293
Células HeLa
Seres Humanos
Hidrazonas/farmacologia
Luciferases de Vaga-Lume/genética
Luciferases de Vaga-Lume/metabolismo
Biossíntese de Proteínas
Inibidores da Síntese de Proteínas/farmacologia
Capuzes de RNA/genética
Capuzes de RNA/metabolismo
Dobramento de RNA
RNA Mensageiro/química
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Pontos de Checagem da Fase S do Ciclo Celular/genética
Tiazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4EGI-1 compound); 0 (5' Untranslated Regions); 0 (Hydrazones); 0 (Protein Synthesis Inhibitors); 0 (RNA Caps); 0 (RNA, Messenger); 0 (Thiazoles); EC 1.13.12.7 (Luciferases, Firefly); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170820
[St] Status:MEDLINE
[do] DOI:10.1261/rna.063040.117


  7 / 2265 MEDLINE  
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[PMID]:28781236
[Au] Autor:Pausch P; Müller-Esparza H; Gleditzsch D; Altegoer F; Randau L; Bange G
[Ad] Endereço:LOEWE Center for Synthetic Microbiology (Synmikro) and Faculty of Chemistry, Philipps-University-Marburg, Hans-Meerwein-Strasse C07, 35043 Marburg, Germany.
[Ti] Título:Structural Variation of Type I-F CRISPR RNA Guided DNA Surveillance.
[So] Source:Mol Cell;67(4):622-632.e4, 2017 Aug 17.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CRISPR-Cas systems are prokaryotic immune systems against invading nucleic acids. Type I CRISPR-Cas systems employ highly diverse, multi-subunit surveillance Cascade complexes that facilitate duplex formation between crRNA and complementary target DNA for R-loop formation, retention, and DNA degradation by the subsequently recruited nuclease Cas3. Typically, the large subunit recognizes bona fide targets through the PAM (protospacer adjacent motif), and the small subunit guides the non-target DNA strand. Here, we present the Apo- and target-DNA-bound structures of the I-Fv (type I-F variant) Cascade lacking the small and large subunits. Large and small subunits are functionally replaced by the 5' terminal crRNA cap Cas5fv and the backbone protein Cas7fv, respectively. Cas5fv facilitates PAM recognition from the DNA major groove site, in contrast to all other described type I systems. Comparison of the type I-Fv Cascade with an anti-CRISPR protein-bound I-F Cascade reveals that the type I-Fv structure differs substantially at known anti-CRISPR protein target sites and might therefore be resistant to viral Cascade interception.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Proteínas Associadas a CRISPR/metabolismo
Sistemas CRISPR-Cas
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas
DNA/metabolismo
Endonucleases/metabolismo
Ácidos Nucleicos Heteroduplexes/metabolismo
RNA Guia/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Sítios de Ligação
Proteínas Associadas a CRISPR/química
Proteínas Associadas a CRISPR/genética
Cristalografia por Raios X
DNA/química
DNA/genética
Endonucleases/química
Endonucleases/genética
Escherichia coli/enzimologia
Escherichia coli/genética
Modelos Moleculares
Conformação de Ácido Nucleico
Ácidos Nucleicos Heteroduplexes/química
Ácidos Nucleicos Heteroduplexes/genética
Ligação Proteica
Conformação Proteica
Capuzes de RNA/metabolismo
RNA Guia/química
RNA Guia/genética
Shewanella putrefaciens/enzimologia
Shewanella putrefaciens/genética
Relação Estrutura-Atividade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (CRISPR-Associated Proteins); 0 (Nucleic Acid Heteroduplexes); 0 (RNA Caps); 0 (RNA, Guide); 9007-49-2 (DNA); EC 3.1.- (Endonucleases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170808
[St] Status:MEDLINE


  8 / 2265 MEDLINE  
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[PMID]:28698206
[Au] Autor:Szydlowski M; Prochorec-Sobieszek M; Szumera-Cieckiewicz A; Derezinska E; Hoser G; Wasilewska D; Szymanska-Giemza O; Jablonska E; Bialopiotrowicz E; Sewastianik T; Polak A; Czardybon W; Galezowski M; Windak R; Zaucha JM; Warzocha K; Brzózka K; Juszczynski P
[Ad] Endereço:Department of Experimental Hematology and.
[Ti] Título:Expression of PIM kinases in Reed-Sternberg cells fosters immune privilege and tumor cell survival in Hodgkin lymphoma.
[So] Source:Blood;130(12):1418-1429, 2017 Sep 21.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Reed-Sternberg (RS) cells of classical Hodgkin lymphoma (cHL) express multiple immunoregulatory proteins that shape the cHL microenvironment and allow tumor cells to evade immune surveillance. Expression of certain immunoregulatory proteins is modulated by prosurvival transcription factors, such as NFκB and STATs. Because these factors also induce expression of the oncogenic PIM1/2/3 serine/threonine kinases, and as PIMs modulate transcriptional activity of NFκB and STATs, we hypothesized that these kinases support RS cell survival and foster their immune privilege. Here, we investigated PIM1/2/3 expression in cHL and assessed their role in developing RS cell immune privilege and survival. PIM1/2/3 were ubiquitously expressed in primary and cultured RS cells, and their expression was driven by JAK-STAT and NFκB activity. Genetic or chemical PIM inhibition with a newly developed pan-PIM inhibitor, SEL24-B489, induced RS cell apoptosis. PIM inhibition decreased cap-dependent protein translation, blocked JAK-STAT signaling, and markedly attenuated NFκB-dependent gene expression. In a cHL xenograft model, SEL24-B489 delayed tumor growth by 95.8% ( = .0002). Furthermore, SEL24-B489 decreased the expression of multiple molecules engaged in developing the immunosuppressive microenvironment, including galectin-1 and PD-L1/2. In coculture experiments, T cells incubated with SEL24-B489-treated RS cells exhibited higher expression of activation markers than T cells coincubated with control RS cells. Taken together, our data indicate that PIM kinases in cHL exhibit pleiotropic effects, orchestrating tumor immune escape and supporting RS cell survival. Inhibition of PIM kinases decreases RS cell viability and disrupts signaling circuits that link these cells with their niches. Thus, PIM kinases are promising therapeutic targets in cHL.
[Mh] Termos MeSH primário: Doença de Hodgkin/enzimologia
Doença de Hodgkin/imunologia
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas c-pim-1/metabolismo
Proteínas Proto-Oncogênicas/metabolismo
Células de Reed-Sternberg/enzimologia
Células de Reed-Sternberg/patologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Sobrevivência Celular
Quimiocinas/metabolismo
Regulação para Baixo
Doença de Hodgkin/patologia
Seres Humanos
Imunomodulação
Janus Quinases/metabolismo
Ativação Linfocitária/imunologia
NF-kappa B/metabolismo
Biossíntese de Proteínas
Capuzes de RNA/metabolismo
Fatores de Transcrição STAT/metabolismo
Transdução de Sinais
Linfócitos T/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chemokines); 0 (NF-kappa B); 0 (PIM2 protein, human); 0 (Proto-Oncogene Proteins); 0 (RNA Caps); 0 (STAT Transcription Factors); EC 2.7.10.2 (Janus Kinases); EC 2.7.11.1 (PIM1 protein, human); EC 2.7.11.1 (PIM3 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-pim-1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-01-760702


  9 / 2265 MEDLINE  
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[PMID]:28666355
[Au] Autor:Rydzik AM; Warminski M; Sikorski PJ; Baranowski MR; Walczak S; Kowalska J; Zuberek J; Lukaszewicz M; Nowak E; W Claridge TD; Darzynkiewicz E; Nowotny M; Jemielity J
[Ad] Endereço:Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw, Poland.
[Ti] Título:mRNA cap analogues substituted in the tetraphosphate chain with CX2: identification of O-to-CCl2 as the first bridging modification that confers resistance to decapping without impairing translation.
[So] Source:Nucleic Acids Res;45(15):8661-8675, 2017 Sep 06.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Analogues of the mRNA 5'-cap are useful tools for studying mRNA translation and degradation, with emerging potential applications in novel therapeutic interventions including gene therapy. We report the synthesis of novel mono- and dinucleotide cap analogues containing dihalogenmethylenebisphosphonate moiety (i.e. one of the bridging O atom substituted with CCl2 or CF2) and their properties in the context of cellular translational and decapping machineries, compared to phosphate-unmodified and previously reported CH2-substituted caps. The analogues were bound tightly to eukaryotic translation initiation factor 4E (eIF4E), with CCl2-substituted analogues having the highest affinity. When incorporated into mRNA, the CCl2-substituted dinucleotide most efficiently promoted cap-dependent translation. Moreover, the CCl2-analogues were potent inhibitors of translation in rabbit reticulocyte lysate. The crystal structure of eIF4E in complex with the CCl2-analogue revealed a significantly different ligand conformation compared to that of the unmodified cap analogue, which likely contributes to the improved binding. Both CCl2- and CF2- analogues showed lower susceptibility to hydrolysis by the decapping scavenger enzyme (DcpS) and, when incorporated into RNA, conferred stability against major cellular decapping enzyme (Dcp2) to transcripts. Furthermore, the use of difluoromethylene cap analogues was exemplified by the development of 19F NMR assays for DcpS activity and eIF4E binding.
[Mh] Termos MeSH primário: Endorribonucleases/metabolismo
Biossíntese de Proteínas/efeitos dos fármacos
Análogos de Capuz de RNA/farmacologia
Processamento Pós-Transcricional do RNA/efeitos dos fármacos
RNA Mensageiro/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação/efeitos dos fármacos
Cristalografia por Raios X
Fosfatos de Dinucleosídeos/química
Fosfatos de Dinucleosídeos/metabolismo
Fator de Iniciação 4E em Eucariotos/metabolismo
Células HeLa
Seres Humanos
Camundongos
Modelos Moleculares
Análogos de Capuz de RNA/química
Análogos de Capuz de RNA/metabolismo
Capuzes de RNA/química
Capuzes de RNA/efeitos dos fármacos
Capuzes de RNA/metabolismo
RNA Mensageiro/química
RNA Mensageiro/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dinucleoside Phosphates); 0 (Eukaryotic Initiation Factor-4E); 0 (RNA Cap Analogs); 0 (RNA Caps); 0 (RNA, Messenger); 0 (mRNA decapping enzymes); EC 3.1.- (Endoribonucleases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170702
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx569


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[PMID]:28646652
[Au] Autor:Sikora D; Rocheleau L; Brown EG; Pelchat M
[Ad] Endereço:Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
[Ti] Título:Influenza A virus cap-snatches host RNAs based on their abundance early after infection.
[So] Source:Virology;509:167-177, 2017 Sep.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The influenza A virus RNA polymerase cleaves the 5' ends of host RNAs and uses these RNA fragments as primers for viral mRNA synthesis. We performed deep sequencing of the 5' host-derived ends of the eight viral mRNAs of influenza A/Puerto Rico/8/1934 (H1N1) virus in infected A549 cells, and compared the population to those of A/Hong Kong/1/1968 (H3N2) and A/WSN/1933 (H1N1). In the three strains, the viral RNAs target different populations of host RNAs. Host RNAs are cap-snatched based on their abundance, and we found that RNAs encoding proteins involved in metabolism are overrepresented in the cap-snatched populations. Because this overrepresentation could be a reflection of the host response early after infection, and thus of the increased availability of these transcripts, our results suggest that host RNAs are cap-snatched mainly based on their abundance without preferential targeting.
[Mh] Termos MeSH primário: Células Epiteliais/virologia
Interações Hospedeiro-Patógeno
Vírus da Influenza A Subtipo H1N1/genética
Vírus da Influenza A Subtipo H3N2/genética
Capuzes de RNA/genética
Capuzes de RNA/metabolismo
Replicação Viral
[Mh] Termos MeSH secundário: Linhagem Celular
Variação Genética
Seres Humanos
Análise de Sequência de DNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA Caps)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170721
[Lr] Data última revisão:
170721
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170625
[St] Status:MEDLINE



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