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[PMID]:29174815
[Au] Autor:Khadka DB; Park S; Jin Y; Han J; Kwon Y; Cho WJ
[Ad] Endereço:College of Pharmacy, Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
[Ti] Título:Design, synthesis, and biological evaluation of 1,3-diarylisoquinolines as novel topoisomerase I catalytic inhibitors.
[So] Source:Eur J Med Chem;143:200-215, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:With a goal of identifying potent topoisomerase (topo) inhibitor, the C4-aromatic ring of the anticancer agent, 3,4-diarylisoquinolone, was strategically shifted to design 1,3-diarylisoquinoline. Twenty-two target compounds were synthesized in three simple and efficient steps. The 1,3-diarylisoquinolines exhibited potent anti-proliferative effects on cancer cells but few compounds spared non-cancerous cells. Inhibition of topo I/IIα-mediated DNA relaxation by several derivatives was greater than that by camptothecin (CPT)/etoposide even at low concentration (20 µM). In addition, these compounds had little or no effect on polymerization of tubulin. A series of biological evaluations performed with the most potent derivative 4cc revealed that the compound is a non-intercalative topo I catalytic inhibitor interacting with free topo I. Collectively, the potent cytotoxic effect on cancer cells including the drug resistance ones, absence of lethal effect on normal cells, and different mechanism of action than topo I poisons suggest that the 1,3-diarylisoquinolines might be a promising class of anticancer agents worthy of further pursuit.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
DNA Topoisomerases Tipo I/metabolismo
Desenho de Drogas
Isoquinolinas/farmacologia
Inibidores da Topoisomerase I/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Biocatálise
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Isoquinolinas/síntese química
Isoquinolinas/química
Estrutura Molecular
Polimerização/efeitos dos fármacos
Relação Estrutura-Atividade
Inibidores da Topoisomerase I/síntese química
Inibidores da Topoisomerase I/química
Tubulina (Proteína)/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Isoquinolines); 0 (Topoisomerase I Inhibitors); 0 (Tubulin); EC 5.99.1.2 (DNA Topoisomerases, Type I)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status: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


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[PMID]:28973046
[Au] Autor:Visone V; Han W; Perugino G; Del Monaco G; She Q; Rossi M; Valenti A; Ciaramella M
[Ad] Endereço:Institute of Biosciences and Bioresources, National Research Council of Italy, Napoli, Italy.
[Ti] Título:In vivo and in vitro protein imaging in thermophilic archaea by exploiting a novel protein tag.
[So] Source:PLoS One;12(10):e0185791, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein imaging, allowing a wide variety of biological studies both in vitro and in vivo, is of great importance in modern biology. Protein and peptide tags fused to proteins of interest provide the opportunity to elucidate protein location and functions, detect protein-protein interactions, and measure protein activity and kinetics in living cells. Whereas several tags are suitable for protein imaging in mesophilic organisms, the application of this approach to microorganisms living at high temperature has lagged behind. Archaea provide an excellent and unique model for understanding basic cell biology mechanisms. Here, we present the development of a toolkit for protein imaging in the hyperthermophilic archaeon Sulfolobus islandicus. The system relies on a thermostable protein tag (H5) constructed by engineering the alkylguanine-DNA-alkyl-transferase protein of Sulfolobus solfataricus, which can be covalently labeled using a wide range of small molecules. As a suitable host, we constructed, by CRISPR-based genome-editing technology, a S. islandicus mutant strain deleted for the alkylguanine-DNA-alkyl-transferase gene (Δogt). Introduction of a plasmid-borne H5 gene in this strain led to production of a functional H5 protein, which was successfully labeled with appropriate fluorescent molecules and visualized in cell extracts as well as in Δogt live cells. H5 was fused to reverse gyrase, a peculiar thermophile-specific DNA topoisomerase endowed with positive supercoiling activity, and allowed visualization of the enzyme in living cells. To the best of our knowledge, this is the first report of in vivo imaging of any protein of a thermophilic archaeon, filling an important gap in available tools for cell biology studies in these organisms.
[Mh] Termos MeSH primário: Archaea/metabolismo
Proteínas Arqueais/metabolismo
Sulfolobus solfataricus/metabolismo
Sulfolobus/metabolismo
[Mh] Termos MeSH secundário: DNA Topoisomerases Tipo I/metabolismo
Temperatura Alta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Archaeal Proteins); EC 5.99.1.2 (DNA Topoisomerases, Type I)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185791


  4 / 4416 MEDLINE  
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Stavale, Joäo N
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[PMID]:28966033
[Au] Autor:Mackay A; Burford A; Carvalho D; Izquierdo E; Fazal-Salom J; Taylor KR; Bjerke L; Clarke M; Vinci M; Nandhabalan M; Temelso S; Popov S; Molinari V; Raman P; Waanders AJ; Han HJ; Gupta S; Marshall L; Zacharoulis S; Vaidya S; Mandeville HC; Bridges LR; Martin AJ; Al-Sarraj S; Chandler C; Ng HK; Li X; Mu K; Trabelsi S; Brahim DH; Kisljakov AN; Konovalov DM; Moore AS; Carcaboso AM; Sunol M; de Torres C; Cruz O; Mora J; Shats LI; Stavale JN; Bidinotto LT; Reis RM; Entz-Werle N; Farrell M; Cryan J; Crimmins D; Caird J; Pears J; Monje M; Debily MA
[Ad] Endereço:Division of Molecular Pathology, The Institute of Cancer Research, London, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
[Ti] Título:Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.
[So] Source:Cancer Cell;32(4):520-537.e5, 2017 Oct 09.
[Is] ISSN:1878-3686
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.
[Mh] Termos MeSH primário: Neoplasias do Tronco Encefálico/genética
Glioma/genética
Histonas/genética
Mutação
[Mh] Termos MeSH secundário: Adolescente
Neoplasias do Tronco Encefálico/patologia
Proteínas de Ciclo Celular/genética
Criança
Pré-Escolar
DNA Topoisomerases Tipo I/genética
Exoma
Proteínas F-Box/genética
Proteína 7 com Repetições F-Box-WD
Feminino
Dosagem de Genes
Glioma/patologia
Seres Humanos
Lactente
Recém-Nascido
Masculino
Proteínas Proto-Oncogênicas/genética
Proteínas Repressoras/genética
Ubiquitina-Proteína Ligases/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
0 (BCOR protein, human); 0 (Cell Cycle Proteins); 0 (F-Box Proteins); 0 (F-Box-WD Repeat-Containing Protein 7); 0 (FBXW7 protein, human); 0 (Histones); 0 (Proto-Oncogene Proteins); 0 (Repressor Proteins); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 5.99.1.2 (DNA Topoisomerases, Type I); EC 5.99.1.2 (DNA topoisomerase III)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE


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[PMID]:28887044
[Au] Autor:Liu Y; Berrido AM; Hua ZC; Tse-Dinh YC; Leng F
[Ad] Endereço:Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, United States; Department of Chemistry & Biochemistry, Florida International University, Miami, FL 33199, United States; School of Life Sciences, Nanjing University, Nanjing 210023, Jiangsu Province, PR China.
[Ti] Título:Biochemical and biophysical properties of positively supercoiled DNA.
[So] Source:Biophys Chem;230:68-73, 2017 Nov.
[Is] ISSN:1873-4200
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:In this paper we successfully developed a procedure to generate the (+) supercoiled (sc) plasmid DNA template pZXX6 in the milligram range. With the availability of the (+) sc DNA, we are able to characterize and compare certain biochemical and biophysical properties of (+) sc, (-) sc, and relaxed (rx) DNA molecules using different techniques, such as UV melting, circular dichroism, and fluorescence spectrometry. Our results show that (+) sc, (-) sc, and rx DNA templates can only be partially melted due to the fact that these DNA templates are closed circular DNA molecules and the two DNA strands cannot be completely separated upon denaturation at high temperatures. We also find that the fluorescence intensity of a DNA-binding dye SYTO12 upon binding to the (-) sc DNA is significantly higher than that of its binding to the (+) sc DNA. This unique property may be used to differentiate the (-) sc DNA from the (+) sc DNA. Additionally, we demonstrate that E. coli topoisomerase I cannot relax the (+) sc DNA. In contrast, E. coli DNA gyrase can efficiently convert the (+) sc DNA to the (-) sc DNA. Furthermore, our dialysis competition assays show that DNA intercalators prefer binding to the (-) sc DNA.
[Mh] Termos MeSH primário: DNA Super-Helicoidal/química
[Mh] Termos MeSH secundário: Dicroísmo Circular
DNA Girase/metabolismo
DNA Topoisomerases Tipo I/metabolismo
DNA Super-Helicoidal/metabolismo
Eletroforese em Gel de Ágar
Escherichia coli/metabolismo
Corantes Fluorescentes/química
Corantes Fluorescentes/metabolismo
Substâncias Intercalantes/química
Substâncias Intercalantes/metabolismo
Desnaturação de Ácido Nucleico/efeitos da radiação
Plasmídeos/genética
Plasmídeos/metabolismo
Espectrometria de Fluorescência
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Superhelical); 0 (Fluorescent Dyes); 0 (Intercalating Agents); EC 5.99.1.2 (DNA Topoisomerases, Type I); EC 5.99.1.3 (DNA Gyrase)
[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:170910
[St] Status:MEDLINE


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[PMID]:28877996
[Au] Autor:Sobinoff AP; Allen JA; Neumann AA; Yang SF; Walsh ME; Henson JD; Reddel RR; Pickett HA
[Ad] Endereço:Telomere Length Regulation Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW, Australia.
[Ti] Título:BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres.
[So] Source:EMBO J;36(19):2907-2919, 2017 Oct 02.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Alternative lengthening of telomeres (ALT) is a telomere lengthening pathway that predominates in aggressive tumors of mesenchymal origin; however, the underlying mechanism of telomere synthesis is not fully understood. Here, we show that the BLM-TOP3A-RMI (BTR) dissolvase complex is required for ALT-mediated telomere synthesis. We propose that recombination intermediates formed during strand invasion are processed by the BTR complex, initiating rapid and extensive POLD3-dependent telomere synthesis followed by dissolution, with no overall exchange of telomeric DNA. This process is counteracted by the SLX4-SLX1-ERCC4 complex, which promotes resolution of the recombination intermediate, resulting in telomere exchange in the absence of telomere extension. Our data are consistent with ALT being a conservative DNA replication process, analogous to break-induced replication, which is dependent on BTR and counteracted by SLX4 complex-mediated resolution events.
[Mh] Termos MeSH primário: Replicação do DNA/genética
RecQ Helicases/fisiologia
Recombinases/fisiologia
Recombinação Genética/genética
Homeostase do Telômero/genética
[Mh] Termos MeSH secundário: Células Cultivadas
DNA Topoisomerases Tipo I/metabolismo
DNA Topoisomerases Tipo I/fisiologia
DNA Polimerase Dirigida por DNA/metabolismo
DNA Polimerase Dirigida por DNA/fisiologia
Seres Humanos
Complexos Multienzimáticos/metabolismo
Complexos Multienzimáticos/fisiologia
RecQ Helicases/metabolismo
Recombinases/metabolismo
Telômero/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Multienzyme Complexes); 0 (Recombinases); EC 2.7.7.- (DNA synthesome); EC 2.7.7.7 (DNA-Directed DNA Polymerase); EC 3.1.- (SLX4 protein, human); EC 3.6.1.- (Bloom syndrome protein); EC 3.6.4.12 (RecQ Helicases); EC 5.99.1.2 (DNA Topoisomerases, Type I); EC 5.99.1.2 (DNA topoisomerase III)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201796889


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[PMID]:28870917
[Au] Autor:Bar JK; Lis-Nawara A; Grelewski P; Noga L; Grzebieniak Z; Jelen M
[Ad] Endereço:Department of Immunopathology and Molecular Biology, Wroclaw Medical University, Wroclaw, Poland julia.bar@umed.wroc.pl.
[Ti] Título:The Association Between HSP90/topoisomerase I Immunophenotype and the Clinical Features of Colorectal Cancers in Respect to Gene Status.
[So] Source:Anticancer Res;37(9):4953-4960, 2017 09.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:AIM: The aim of this study was to investigate heat shock protein 90 (HSP90) and topoisomerase I (Topo I) expression and the association between both proteins and clinicopathological parameters of colorectal cancer (CRC), in order to describe their role in tumor biology regarding to Kirsten Ras (KRAS) - positive/negative cases. MATERIALS AND METHODS: Expression of HSP90 and Topo I, and KRAS gene mutations were estimated in primary CRCs. RESULTS: HSP90/Topo I immunophenotype correlated with gender, Duke staging, tumor grade and lymph node metastasis (p<0.01). Positive correlation was found between KRAS mutation and HSP90 expression (p=0.02). HSP90, Topo I expression, and co-expression of HSP90/Topo I correlated with unfavorable parameters of CRCs in respect to KRAS gene status (p<0.001). CONCLUSION: Our results revealed that cooperation between HSP90 and Topo I expression exists in CRCs, independently of KRAS gene status, suggesting that co-expression of both proteins might be considered as a double target on individual tumor cells.
[Mh] Termos MeSH primário: Adenocarcinoma/secundário
Neoplasias Colorretais/patologia
DNA Topoisomerases Tipo I/metabolismo
Proteínas de Choque Térmico HSP90/metabolismo
Mutação
Proteínas Proto-Oncogênicas p21(ras)/genética
[Mh] Termos MeSH secundário: Adenocarcinoma/genética
Adenocarcinoma/metabolismo
Adulto
Idoso
Idoso de 80 Anos ou mais
Biomarcadores Tumorais/genética
Biomarcadores Tumorais/metabolismo
Neoplasias Colorretais/genética
Neoplasias Colorretais/metabolismo
Feminino
Seguimentos
Seres Humanos
Imunofenotipagem
Metástase Linfática
Masculino
Meia-Idade
Gradação de Tumores
Estadiamento de Neoplasias
Prognóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (HSP90 Heat-Shock Proteins); 0 (KRAS protein, human); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)); EC 5.99.1.2 (DNA Topoisomerases, Type I); EC 5.99.1.2 (TOP1 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE


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[PMID]:28843989
[Au] Autor:Banda S; Cao N; Tse-Dinh YC
[Ad] Endereço:Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA; Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USA.
[Ti] Título:Distinct Mechanism Evolved for Mycobacterial RNA Polymerase and Topoisomerase I Protein-Protein Interaction.
[So] Source:J Mol Biol;429(19):2931-2942, 2017 Sep 15.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We report here a distinct mechanism of interaction between topoisomerase I and RNA polymerase in Mycobacterium tuberculosis and Mycobacterium smegmatis that has evolved independently from the previously characterized interaction between bacterial topoisomerase I and RNA polymerase. Bacterial DNA topoisomerase I is responsible for preventing the hyper-negative supercoiling of genomic DNA. The association of topoisomerase I with RNA polymerase during transcription elongation could efficiently relieve transcription-driven negative supercoiling. Our results demonstrate a direct physical interaction between the C-terminal domains of topoisomerase I (TopoI-CTDs) and the ß' subunit of RNA polymerase of M. smegmatis in the absence of DNA. The TopoI-CTDs in mycobacteria are evolutionarily unrelated in amino acid sequence and three-dimensional structure to the TopoI-CTD found in the majority of bacterial species outside Actinobacteria, including Escherichia coli. The functional interaction between topoisomerase I and RNA polymerase has evolved independently in mycobacteria and E. coli, with distinctively different structural elements of TopoI-CTD utilized for this protein-protein interaction. Zinc ribbon motifs in E. coli TopoI-CTD are involved in the interaction with RNA polymerase. For M. smegmatis TopoI-CTD, a 27-amino-acid tail that is rich in basic residues at the C-terminal end is responsible for the interaction with RNA polymerase. Overexpression of recombinant TopoI-CTD in M. smegmatis competed with the endogenous topoisomerase I for protein-protein interactions with RNA polymerase. The TopoI-CTD overexpression resulted in decreased survival following treatment with antibiotics and hydrogen peroxide, supporting the importance of the protein-protein interaction between topoisomerase I and RNA polymerase during stress response of mycobacteria.
[Mh] Termos MeSH primário: DNA Topoisomerases Tipo I/metabolismo
RNA Polimerases Dirigidas por DNA/metabolismo
Mycobacterium smegmatis/enzimologia
Mycobacterium tuberculosis/enzimologia
Mapas de Interação de Proteínas
[Mh] Termos MeSH secundário: Escherichia coli/enzimologia
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.7.6 (DNA-Directed RNA Polymerases); EC 5.99.1.2 (DNA Topoisomerases, Type I)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170828
[St] Status:MEDLINE


  9 / 4416 MEDLINE  
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[PMID]:28797568
[Au] Autor:Koosha F; Neshasteh-Riz A; Takavar A; Eyvazzadeh N; Mazaheri Z; Eynali S; Mousavi M
[Ad] Endereço:Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran.
[Ti] Título:The combination of A-966492 and Topotecan for effective radiosensitization on glioblastoma spheroids.
[So] Source:Biochem Biophys Res Commun;491(4):1092-1097, 2017 Sep 30.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Radiotherapy is one of the modalities in the treatment of glioblastoma patients, but glioma tumors are resistant to radiation and also chemotherapy drugs. Thus, researchers are investigating drugs which have radiosensitization capabilities in order to improve radiotherapy. PARP enzymes and topoisomerase I enzymes have a critical role in repairing DNA damage in tumor cells. Thus, inhibiting activity of these enzymes helps stop DNA damage repair and increase DSB lethal damages. In the current study, we investigated the combination of TPT as a topoisomerase I inhibitor, and A-966492 as a novel PARP inhibitor for further radiosensitization. U87MG cells (a human glioblastoma cell line) were cultured in Poly-Hema coated flasks to reach 300 µm-diameter spheroids. Treatments were accomplished by using non-toxic concentrations of A-966492 and Topotecan. The surviving fraction of treated cells was determined by clonogenic assay after treatment with drugs and 6 MV X-ray. The γ-H2AX expression was measured by an immunofluorescence staining method to examine the influence of A-966492, TPT and radiation on the induction of double stranded DNA breaks. Treatments using the A-966492 drug were conducted in concentration of 1 µM. Combining A-966492 and TPT with radiation yielded enhanced cell killing, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER ) 1.39 and 1.16 respectively. Radio- and chemo-sensitization was further enhanced when A-966492 was combined with both X-ray and TPT, with SER of 1.53. Also γ-H2AX expression was higher in the group treated with a combination of drugs and radiation. A-966492 is an effective PARP inhibitor and has significant radio-sensitivity on U87MG spheroids. By accumulating cells in the S phase and by inhibiting the DNA damage repair, TPT enhanced radio-sensitivity. A-966492 combined with TPT as a topoisomerase I inhibitor had additive radio-sensitizing effects. As a result, applying PARP and topoisomerase I inhibitors can be a suitable strategy for improving radiotherapy in clinics.
[Mh] Termos MeSH primário: Benzimidazóis/farmacologia
Glioblastoma/tratamento farmacológico
Esferoides Celulares/efeitos dos fármacos
Inibidores da Topoisomerase I/farmacologia
Topotecan/farmacologia
[Mh] Termos MeSH secundário: Benzimidazóis/administração & dosagem
Linhagem Celular Tumoral
DNA Topoisomerases Tipo I/metabolismo
Seres Humanos
Tolerância a Radiação/efeitos dos fármacos
Relação Estrutura-Atividade
Inibidores da Topoisomerase I/administração & dosagem
Topotecan/administração & dosagem
Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide); 0 (Benzimidazoles); 0 (Topoisomerase I Inhibitors); 7M7YKX2N15 (Topotecan); EC 5.99.1.2 (DNA Topoisomerases, Type I)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE


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[PMID]:28756025
[Au] Autor:Li D; Lv B; Wang Q; Liu Y; Zhuge Q
[Ad] Endereço:Key Lab of Forest Genetics and Biotechnology, Nanjing Forestry University, 159 Longpan Road, Nanjing 210037, China. Electronic address: dwli@njfu.edu.cn.
[Ti] Título:Direct observation of positive supercoils introduced by reverse gyrase through atomic force microscopy.
[So] Source:Bioorg Med Chem Lett;27(17):4086-4090, 2017 09 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Reverse gyrase is a hyperthermophilic enzyme that can introduce positive supercoiling in substrate DNA. It is showed in our studies that positive DNA supercoils were induced in both pBR322 vector and an artificially synthesized mini-plasmid DNA by reverse gyrase. The left-handed structures adopted by positively supercoiled DNA molecules could be identified from their right-handed topoisomers through atomic force microscopic examination. Additional structural comparisons revealed that positively supercoiled DNA molecule AFM images exhibited increased contour lengths. Moreover, enzymatic assays showed that the positively supercoiled DNA could not be cleaved by T7 endonuclease. Together, this suggests that the overwound structure of positive supercoils could prevent genomic duplex DNA from randomly forming single-stranded DNA regions and intra-stranded secondary structures.
[Mh] Termos MeSH primário: DNA Topoisomerases Tipo I/metabolismo
DNA Super-Helicoidal/biossíntese
[Mh] Termos MeSH secundário: DNA Topoisomerases Tipo I/química
DNA Super-Helicoidal/química
Microscopia de Força Atômica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DNA, Superhelical); EC 5.99.1.- (DNA reverse gyrase); EC 5.99.1.2 (DNA Topoisomerases, Type I)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170731
[St] Status:MEDLINE



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