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  1 / 1720 MEDLINE  
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[PMID]:29065309
[Au] Autor:Liu Y; Mattila J; Ventelä S; Yadav L; Zhang W; Lamichane N; Sundström J; Kauko O; Grénman R; Varjosalo M; Westermarck J; Hietakangas V
[Ad] Endereço:Department of Biosciences, University of Helsinki, 00790 Helsinki, Finland; Institute of Biotechnology, University of Helsinki, 00790 Helsinki, Finland.
[Ti] Título:PWP1 Mediates Nutrient-Dependent Growth Control through Nucleolar Regulation of Ribosomal Gene Expression.
[So] Source:Dev Cell;43(2):240-252.e5, 2017 Oct 23.
[Is] ISSN:1878-1551
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ribosome biogenesis regulates animal growth and is controlled by nutrient-responsive mTOR signaling. How ribosome biogenesis is regulated during the developmental growth of animals and how nutrient-responsive signaling adjusts ribosome biogenesis in this setting have remained insufficiently understood. We uncover PWP1 as a chromatin-associated regulator of developmental growth with a conserved role in RNA polymerase I (Pol I)-mediated rRNA transcription. We further observed that PWP1 epigenetically maintains the rDNA loci in a transcription-competent state. PWP1 responds to nutrition in Drosophila larvae via mTOR signaling through gene expression and phosphorylation, which controls the nucleolar localization of dPWP1. Our data further imply that dPWP1 acts synergistically with mTOR signaling to regulate the nucleolar localization of TFIIH, a known elongation factor of Pol I. Ribosome biogenesis is often deregulated in cancer, and we demonstrate that high PWP1 levels in human head and neck squamous cell carcinoma tumors are associated with poor prognosis.
[Mh] Termos MeSH primário: Carcinoma de Células Escamosas/patologia
Proteínas de Ciclo Celular/metabolismo
Nucléolo Celular/metabolismo
Alimentos
Regulação da Expressão Gênica
Neoplasias de Cabeça e Pescoço/patologia
Proteínas Nucleares/metabolismo
Ribossomos/genética
[Mh] Termos MeSH secundário: Animais
Carcinoma de Células Escamosas/genética
Carcinoma de Células Escamosas/metabolismo
Proteínas de Ciclo Celular/genética
Cromatina/genética
DNA Ribossômico/genética
Drosophila/genética
Drosophila/crescimento & desenvolvimento
Drosophila/metabolismo
Neoplasias de Cabeça e Pescoço/genética
Neoplasias de Cabeça e Pescoço/metabolismo
Seres Humanos
Proteínas Nucleares/genética
Fosforilação
Prognóstico
RNA Polimerase I/metabolismo
RNA Ribossômico/genética
Transdução de Sinais
Taxa de Sobrevida
Serina-Treonina Quinases TOR/metabolismo
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (Chromatin); 0 (DNA, Ribosomal); 0 (Nuclear Proteins); 0 (PWP1 protein, human); 0 (RNA, Ribosomal); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.7.6 (RNA Polymerase I)
[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:171025
[St] Status:MEDLINE


  2 / 1720 MEDLINE  
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[PMID]:28977560
[Au] Autor:Shen W; Sun H; De Hoyos CL; Bailey JK; Liang XH; Crooke ST
[Ad] Endereço:Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
[Ti] Título:Dynamic nucleoplasmic and nucleolar localization of mammalian RNase H1 in response to RNAP I transcriptional R-loops.
[So] Source:Nucleic Acids Res;45(18):10672-10692, 2017 Oct 13.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:An R-loop is a DNA:RNA hybrid formed during transcription when a DNA duplex is invaded by a nascent RNA transcript. R-loops accumulate in nucleoli during RNA polymerase I (RNAP I) transcription. Here, we report that mammalian RNase H1 enriches in nucleoli and co-localizes with R-loops in cultured human cells. Co-migration of RNase H1 and R-loops from nucleoli to perinucleolar ring structures was observed upon inhibition of RNAP I transcription. Treatment with camptothecin which transiently stabilized nucleolar R-loops recruited RNase H1 to the nucleoli. It has been reported that the absence of Topoisomerase and RNase H activity in Escherichia coli or Saccharomyces cerevisiae caused R-loop accumulation along rDNA. We found that the distribution of RNase H1 and Top1 along rDNA coincided at sites where R-loops accumulated in mammalian cells. Loss of either RNase H1 or Top1 caused R-loop accumulation, and the accumulation of R-loops was exacerbated when both proteins were depleted. Importantly, we observed that protein levels of Top1 were negatively correlated with the abundance of RNase H1. We conclude that Top1 and RNase H1 are partially functionally redundant in mammalian cells to suppress RNAP I transcription-associate R-loops.
[Mh] Termos MeSH primário: Nucléolo Celular/genética
DNA Ribossômico/química
RNA Polimerase I/metabolismo
Ribonuclease H/análise
Transcrição Genética
[Mh] Termos MeSH secundário: Animais
Camptotecina/farmacologia
Nucléolo Celular/efeitos dos fármacos
Nucléolo Celular/enzimologia
Dano ao DNA
DNA Topoisomerases Tipo I/análise
DNA Ribossômico/metabolismo
Células HEK293
Células HeLa
Seres Humanos
Camundongos Knockout
Domínios Proteicos
RNA/química
RNA Polimerase I/análise
Ribonuclease H/química
Ribonuclease H/metabolismo
Transcrição Genética/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Ribosomal); 63231-63-0 (RNA); EC 2.7.7.- (RPA194 protein, human); EC 2.7.7.6 (RNA Polymerase I); EC 3.1.26.4 (Ribonuclease H); EC 3.1.26.4 (ribonuclease HI); EC 5.99.1.2 (DNA Topoisomerases, Type I); EC 5.99.1.2 (TOP1 protein, human); XT3Z54Z28A (Camptothecin)
[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:171005
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx710


  3 / 1720 MEDLINE  
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[PMID]:28893424
[Au] Autor:Appling FD; Lucius AL; Schneider DA
[Ad] Endereço:Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
[Ti] Título:Quantifying the influence of 5'-RNA modifications on RNA polymerase I activity.
[So] Source:Biophys Chem;230:84-88, 2017 Nov.
[Is] ISSN:1873-4200
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:For ensemble and single-molecule analyses of transcription, the use of synthetic transcription elongation complexes has been a versatile and powerful tool. However, structural analyses demonstrate that short RNA substrates, often employed in these assays, would occupy space within the RNA polymerase. Most commercial RNA oligonucleotides do not carry a 5'-triphosphate as would be present on a natural, de novo synthesized RNA. To examine the effects of 5'-moities on transcription kinetics, we measured nucleotide addition and 3'-dinucleotide cleavage by eukaryotic RNA polymerase I using 5'-hydroxyl and 5'-triphosphate RNA substrates. We found that 5' modifications had no discernable effect on the kinetics of nucleotide addition; however, we observed clear, but modest, effects on the rate of backtracking and/or dinucleotide cleavage. These data suggest that the 5'-end may influence RNA polymerase translocation, consistent with previous prokaryotic studies, and these findings may have implications on kinetic barriers that confront RNA polymerases during the transition from initiation to elongation.
[Mh] Termos MeSH primário: RNA Polimerase I/metabolismo
RNA/metabolismo
[Mh] Termos MeSH secundário: Monofosfato de Adenosina/metabolismo
Cinética
Oligorribonucleotídeos/química
Oligorribonucleotídeos/metabolismo
RNA/química
Saccharomyces cerevisiae/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oligoribonucleotides); 415SHH325A (Adenosine Monophosphate); 63231-63-0 (RNA); EC 2.7.7.6 (RNA Polymerase I)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE


  4 / 1720 MEDLINE  
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[PMID]:28846843
[Au] Autor:Appling FD; Schneider DA; Lucius AL
[Ad] Endereço:Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham , Birmingham, Alabama 35294, United States.
[Ti] Título:Multisubunit RNA Polymerase Cleavage Factors Modulate the Kinetics and Energetics of Nucleotide Incorporation: An RNA Polymerase I Case Study.
[So] Source:Biochemistry;56(42):5654-5662, 2017 Oct 24.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:All cellular RNA polymerases are influenced by protein factors that stimulate RNA polymerase-catalyzed cleavage of the nascent RNA. Despite divergence in amino acid sequence, these so-called "cleavage factors" appear to share a common mechanism of action. Cleavage factors associate with the polymerase through a conserved structural element of the polymerase known as the secondary channel or pore. This mode of association enables the cleavage factor to reach through the secondary channel into the polymerase active site to reorient the active site divalent metal ions. This reorientation converts the polymerase active site into a nuclease active site. Interestingly, eukaryotic RNA polymerases I and III (Pols I and III, respectively) have incorporated their cleavage factors as bona fide subunits known as A12.2 and C11, respectively. Although it is clear that A12.2 and C11 dramatically stimulate the polymerase's cleavage activity, it is not known if or how these subunits affect the polymerization mechanism. In this work we have used transient-state kinetic techniques to characterize a Pol I isoform lacking A12.2. Our data clearly demonstrate that the A12.2 subunit profoundly affects the kinetics and energetics of the elementary steps of Pol I-catalyzed nucleotide incorporation. Given the high degree of conservation between polymerase-cleavage factor interactions, these data indicate that cleavage factor-modulated nucleotide incorporation mechanisms may be common to all cellular RNA polymerases.
[Mh] Termos MeSH primário: Nucleotídeos/química
RNA Polimerase I/química
Proteínas de Saccharomyces cerevisiae/química
Saccharomyces cerevisiae/enzimologia
Fatores de Poliadenilação e Clivagem de mRNA/química
[Mh] Termos MeSH secundário: Cinética
Nucleotídeos/metabolismo
RNA Polimerase I/metabolismo
RNA Polimerase III/química
RNA Polimerase III/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Fatores de Poliadenilação e Clivagem de mRNA/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleotides); 0 (Saccharomyces cerevisiae Proteins); 0 (mRNA Cleavage and Polyadenylation Factors); EC 2.7.7.6 (RNA Polymerase I); EC 2.7.7.6 (RNA Polymerase III)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00370


  5 / 1720 MEDLINE  
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[PMID]:28739580
[Au] Autor:Sadian Y; Tafur L; Kosinski J; Jakobi AJ; Wetzel R; Buczak K; Hagen WJ; Beck M; Sachse C; Müller CW
[Ad] Endereço:European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Heidelberg, Germany.
[Ti] Título:Structural insights into transcription initiation by yeast RNA polymerase I.
[So] Source:EMBO J;36(18):2698-2709, 2017 Sep 15.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In eukaryotic cells, RNA polymerase I (Pol I) synthesizes precursor ribosomal RNA (pre-rRNA) that is subsequently processed into mature rRNA. To initiate transcription, Pol I requires the assembly of a multi-subunit pre-initiation complex (PIC) at the ribosomal RNA promoter. In yeast, the minimal PIC includes Pol I, the transcription factor Rrn3, and Core Factor (CF) composed of subunits Rrn6, Rrn7, and Rrn11. Here, we present the cryo-EM structure of the 18-subunit yeast Pol I PIC bound to a transcription scaffold. The cryo-EM map reveals an unexpected arrangement of the DNA and CF subunits relative to Pol I. The upstream DNA is positioned differently than in any previous structures of the Pol II PIC. Furthermore, the TFIIB-related subunit Rrn7 also occupies a different location compared to the Pol II PIC although it uses similar interfaces as TFIIB to contact DNA. Our results show that although general features of eukaryotic transcription initiation are conserved, Pol I and Pol II use them differently in their respective transcription initiation complexes.
[Mh] Termos MeSH primário: RNA Polimerase I/química
RNA Polimerase I/metabolismo
Saccharomyces cerevisiae/enzimologia
Transcrição Genética
[Mh] Termos MeSH secundário: Microscopia Crioeletrônica
DNA Fúngico/metabolismo
Modelos Moleculares
Conformação Proteica
Multimerização Proteica
RNA Ribossômico/biossíntese
Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Fungal); 0 (RNA, Ribosomal); EC 2.7.7.6 (RNA Polymerase I)
[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:170726
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201796958


  6 / 1720 MEDLINE  
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[PMID]:28715449
[Au] Autor:Herdman C; Mars JC; Stefanovsky VY; Tremblay MG; Sabourin-Felix M; Lindsay H; Robinson MD; Moss T
[Ad] Endereço:Laboratory of Growth and Development, St-Patrick Research Group in Basic Oncology, Cancer Division of the Quebec University Hospital Research Centre, Québec, Canada.
[Ti] Título:A unique enhancer boundary complex on the mouse ribosomal RNA genes persists after loss of Rrn3 or UBF and the inactivation of RNA polymerase I transcription.
[So] Source:PLoS Genet;13(7):e1006899, 2017 Jul.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Transcription of the several hundred of mouse and human Ribosomal RNA (rRNA) genes accounts for the majority of RNA synthesis in the cell nucleus and is the determinant of cytoplasmic ribosome abundance, a key factor in regulating gene expression. The rRNA genes, referred to globally as the rDNA, are clustered as direct repeats at the Nucleolar Organiser Regions, NORs, of several chromosomes, and in many cells the active repeats are transcribed at near saturation levels. The rDNA is also a hotspot of recombination and chromosome breakage, and hence understanding its control has broad importance. Despite the need for a high level of rDNA transcription, typically only a fraction of the rDNA is transcriptionally active, and some NORs are permanently silenced by CpG methylation. Various chromatin-remodelling complexes have been implicated in counteracting silencing to maintain rDNA activity. However, the chromatin structure of the active rDNA fraction is still far from clear. Here we have combined a high-resolution ChIP-Seq protocol with conditional inactivation of key basal factors to better understand what determines active rDNA chromatin. The data resolve questions concerning the interdependence of the basal transcription factors, show that preinitiation complex formation is driven by the architectural factor UBF (UBTF) independently of transcription, and that RPI termination and release corresponds with the site of TTF1 binding. They further reveal the existence of an asymmetric Enhancer Boundary Complex formed by CTCF and Cohesin and flanked upstream by phased nucleosomes and downstream by an arrested RNA Polymerase I complex. We find that the Enhancer Boundary Complex is the only site of active histone modification in the 45kbp rDNA repeat. Strikingly, it not only delimits each functional rRNA gene, but also is stably maintained after gene inactivation and the re-establishment of surrounding repressive chromatin. Our data define a poised state of rDNA chromatin and place the Enhancer Boundary Complex as the likely entry point for chromatin remodelling complexes.
[Mh] Termos MeSH primário: Genes de RNAr
Proteínas Pol1 do Complexo de Iniciação de Transcrição/genética
RNA Polimerase I/metabolismo
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Montagem e Desmontagem da Cromatina
Elementos Facilitadores Genéticos
Feminino
Deleção de Genes
Inativação Gênica
Loci Gênicos
Camundongos
Camundongos Knockout
Proteínas Nucleares/genética
Proteínas Nucleares/metabolismo
Região Organizadora do Nucléolo/genética
Região Organizadora do Nucléolo/metabolismo
Proteínas Pol1 do Complexo de Iniciação de Transcrição/metabolismo
Gravidez
RNA Polimerase I/genética
Análise de Sequência de DNA
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nuclear Proteins); 0 (Pol1 Transcription Initiation Complex Proteins); 0 (Rrn3 protein, mouse); 0 (Transcription Factors); 0 (transcription factor UBF); 0 (transcriptional intermediary factor 1); EC 2.7.7.6 (RNA Polymerase I)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006899


  7 / 1720 MEDLINE  
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[PMID]:28636660
[Au] Autor:Assfalg R; Alupei MC; Wagner M; Koch S; Gonzalez OG; Schelling A; Scharffetter-Kochanek K; Iben S
[Ad] Endereço:Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
[Ti] Título:Cellular sensitivity to UV-irradiation is mediated by RNA polymerase I transcription.
[So] Source:PLoS One;12(6):e0179843, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The nucleolus has long been considered to be a pure ribosome factory. However, over the last two decades it became clear that the nucleolus is involved in numerous other functions besides ribosome biogenesis. Our experiments indicate that the activity of RNA polymerase I (Pol I) transcription monitors the integrity of the DNA and influences the response to nucleolar stress as well as the rate of survival. Cells with a repressed ribosomal DNA (rDNA) transcription activity showed an increased and prolonged p53 stabilisation after UVC-irradiation. Furthermore, p53 stabilisation after inhibition and especially after UVC-irradiation might be due to abrogation of the HDM2-p53 degradation pathway by ribosomal proteins (RPs). Apoptosis mediated by highly activated p53 is a typical hallmark of Cockayne syndrome cells and transcriptional abnormalities and the following activation of the RP-HDM2-p53 pathway would be a possible explanation.
[Mh] Termos MeSH primário: RNA Polimerase I/metabolismo
Transcrição Genética/efeitos da radiação
Raios Ultravioleta
[Mh] Termos MeSH secundário: Apoptose/efeitos da radiação
Linhagem Celular
Células HCT116
Seres Humanos
Proteínas Pol1 do Complexo de Iniciação de Transcrição/antagonistas & inibidores
Proteínas Pol1 do Complexo de Iniciação de Transcrição/genética
Proteínas Pol1 do Complexo de Iniciação de Transcrição/metabolismo
Estabilidade Proteica/efeitos da radiação
Proteínas Proto-Oncogênicas c-mdm2/metabolismo
Interferência de RNA
RNA Polimerase I/genética
RNA Ribossômico/metabolismo
RNA Interferente Pequeno/metabolismo
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pol1 Transcription Initiation Complex Proteins); 0 (RNA, Ribosomal); 0 (RNA, Small Interfering); 0 (RRN3 protein, human); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); EC 2.3.2.27 (MDM2 protein, human); EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2); EC 2.7.7.6 (RNA Polymerase I)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170622
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179843


  8 / 1720 MEDLINE  
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[PMID]:28475895
[Au] Autor:Xing YH; Yao RW; Zhang Y; Guo CJ; Jiang S; Xu G; Dong R; Yang L; Chen LL
[Ad] Endereço:State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 2000
[Ti] Título:SLERT Regulates DDX21 Rings Associated with Pol I Transcription.
[So] Source:Cell;169(4):664-678.e16, 2017 May 04.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dysregulated rRNA synthesis by RNA polymerase I (Pol I) is associated with uncontrolled cell proliferation. Here, we report a box H/ACA small nucleolar RNA (snoRNA)-ended long noncoding RNA (lncRNA) that enhances pre-rRNA transcription (SLERT). SLERT requires box H/ACA snoRNAs at both ends for its biogenesis and translocation to the nucleolus. Deletion of SLERT impairs pre-rRNA transcription and rRNA production, leading to decreased tumorigenesis. Mechanistically, SLERT interacts with DEAD-box RNA helicase DDX21 via a 143-nt non-snoRNA sequence. Super-resolution images reveal that DDX21 forms ring-shaped structures surrounding multiple Pol I complexes and suppresses pre-rRNA transcription. Binding by SLERT allosterically alters individual DDX21 molecules, loosens the DDX21 ring, and evicts DDX21 suppression on Pol I transcription. Together, our results reveal an important control of ribosome biogenesis by SLERT lncRNA and its regulatory role in DDX21 ring-shaped arrangements acting on Pol I complexes.
[Mh] Termos MeSH primário: RNA Helicases DEAD-box/metabolismo
RNA Polimerase I/metabolismo
Precursores de RNA/genética
RNA Longo não Codificante/metabolismo
[Mh] Termos MeSH secundário: Sítio Alostérico
Animais
Carcinogênese
Linhagem Celular
Linhagem Celular Tumoral
RNA Helicases DEAD-box/química
Feminino
Técnicas de Inativação de Genes
Seres Humanos
Camundongos
Camundongos Nus
Precursores de RNA/metabolismo
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA Precursors); 0 (RNA, Long Noncoding); EC 2.7.7.6 (RNA Polymerase I); EC 3.6.1.- (DDX21 protein, human); EC 3.6.4.13 (DEAD-box RNA Helicases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170703
[Lr] Data última revisão:
170703
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170506
[St] Status:MEDLINE


  9 / 1720 MEDLINE  
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[PMID]:28369725
[Au] Autor:Lee HC; Wang H; Baladandayuthapani V; Lin H; He J; Jones RJ; Kuiatse I; Gu D; Wang Z; Ma W; Lim J; O'Brien S; Keats J; Yang J; Davis RE; Orlowski RZ
[Ad] Endereço:The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
[Ti] Título:RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma.
[So] Source:Br J Haematol;177(1):80-94, 2017 Apr.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Dysregulation of MYC is frequently implicated in both early and late myeloma progression events, yet its therapeutic targeting has remained a challenge. Among key MYC downstream targets is ribosomal biogenesis, enabling increases in protein translational capacity necessary to support the growth and self-renewal programmes of malignant cells. We therefore explored the selective targeting of ribosomal biogenesis with the small molecule RNA polymerase (pol) I inhibitor CX-5461 in myeloma. CX-5461 induced significant growth inhibition in wild-type (WT) and mutant TP53 myeloma cell lines and primary samples, in association with increases in downstream markers of apoptosis. Moreover, Pol I inhibition overcame adhesion-mediated drug resistance and resistance to conventional and novel agents. To probe the TP53-independent mechanisms of CX-5461, gene expression profiling was performed on isogenic TP53 WT and knockout cell lines and revealed reduction of MYC downstream targets. Mechanistic studies confirmed that CX-5461 rapidly suppressed both MYC protein and MYC mRNA levels. The latter was associated with an increased binding of the RNA-induced silencing complex (RISC) subunits TARBP2 and AGO2, the ribosomal protein RPL5, and MYC mRNA, resulting in increased MYC transcript degradation. Collectively, these studies provide a rationale for the clinical translation of CX-5461 as a novel therapeutic approach to target MYC in myeloma.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Benzotiazóis/farmacologia
Mieloma Múltiplo/genética
Mieloma Múltiplo/metabolismo
Naftiridinas/farmacologia
Proteínas Proto-Oncogênicas c-myc/genética
RNA Polimerase I/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/uso terapêutico
Benzotiazóis/uso terapêutico
Linhagem Celular Tumoral
Modelos Animais de Doenças
Resistência a Medicamentos Antineoplásicos/genética
Expressão Gênica
Perfilação da Expressão Gênica
Seres Humanos
Camundongos
Terapia de Alvo Molecular
Mieloma Múltiplo/tratamento farmacológico
Mieloma Múltiplo/patologia
Mutação
Naftiridinas/uso terapêutico
Proteínas Proto-Oncogênicas c-myc/metabolismo
RNA Polimerase I/metabolismo
Carga Tumoral/efeitos dos fármacos
Proteína Supressora de Tumor p53/genética
Proteína Supressora de Tumor p53/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzothiazoles); 0 (CX 5461); 0 (Naphthyridines); 0 (Proto-Oncogene Proteins c-myc); 0 (Tumor Suppressor Protein p53); EC 2.7.7.6 (RNA Polymerase I)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171121
[Lr] Data última revisão:
171121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.14525


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[PMID]:28340337
[Au] Autor:Engel C; Gubbey T; Neyer S; Sainsbury S; Oberthuer C; Baejen C; Bernecky C; Cramer P
[Ad] Endereço:Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
[Ti] Título:Structural Basis of RNA Polymerase I Transcription Initiation.
[So] Source:Cell;169(1):120-131.e22, 2017 Mar 23.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Transcription initiation at the ribosomal RNA promoter requires RNA polymerase (Pol) I and the initiation factors Rrn3 and core factor (CF). Here, we combine X-ray crystallography and cryo-electron microscopy (cryo-EM) to obtain a molecular model for basal Pol I initiation. The three-subunit CF binds upstream promoter DNA, docks to the Pol I-Rrn3 complex, and loads DNA into the expanded active center cleft of the polymerase. DNA unwinding between the Pol I protrusion and clamp domains enables cleft contraction, resulting in an active Pol I conformation and RNA synthesis. Comparison with the Pol II system suggests that promoter specificity relies on a distinct "bendability" and "meltability" of the promoter sequence that enables contacts between initiation factors, DNA, and polymerase.
[Mh] Termos MeSH primário: Proteínas de Saccharomyces cerevisiae/química
Saccharomyces cerevisiae/química
Iniciação da Transcrição Genética
[Mh] Termos MeSH secundário: Microscopia Crioeletrônica
Cristalografia por Raios X
Modelos Moleculares
Complexos Multiproteicos/química
Complexos Multiproteicos/metabolismo
Complexos Multiproteicos/ultraestrutura
Regiões Promotoras Genéticas
RNA Polimerase I/química
Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/ultraestrutura
Proteínas de Saccharomyces cerevisiae/metabolismo
Proteínas de Saccharomyces cerevisiae/ultraestrutura
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Multiprotein Complexes); 0 (Saccharomyces cerevisiae Proteins); EC 2.7.7.6 (RNA Polymerase I)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170614
[Lr] Data última revisão:
170614
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE



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