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Simon Hartmann, Airat Gubaev, Dagmar Klostermeier
Topoisomerases catalyze the relaxation, supercoiling, catenation, and decatenation of DNA. Gyrase is a bacterial topoisomerase that introduces negative supercoils into DNA in an ATP-dependent reaction. The enzyme consists of two GyrB subunits, containing the ATPase domains, and two GyrA subunits. Nucleotide binding to GyrB causes closing of the N-gate in gyrase, which orients bound DNA for supercoiling. N-gate re-opening after ATP hydrolysis, at the end of the supercoiling reaction, resets the enzyme for subsequent catalytic cycles...
October 11, 2017: Journal of Molecular Biology
Sabrina Khageh Hosseini, Stefanie Kolterer, Marlene Steiner, Victoria von Manstein, Katharina Gerlach, Jörg Trojan, Oliver Waidmann, Stefan Zeuzem, Jörg O Schulze, Steffen Hahn, Dieter Steinhilber, Volker Gatterdam, Robert Tampé, Ricardo M Biondi, Ewgenij Proschak, Martin Zörnig
The transcriptional regulator FUSE Binding Protein 1 (FUBP1) is overexpressed in more than 80% of all human hepatocellular carcinomas (HCCs) and other solid tumor entities including prostate and colorectal carcinoma. FUBP1 expression is required for HCC tumor cell expansion, and it functions as an important pro-proliferative and anti-apoptotic oncoprotein that binds to the single-stranded DNA sequence FUSE to regulate the transcription of a variety of target genes. In this study, we screened an FDA-approved drug library and discovered that the Topoisomerase I (TOP1) inhibitor camptothecin (CPT) and its derivative 7-ethyl-10-hydroxycamptothecin (SN-38), the active irinotecan metabolite that is used in the clinics in combination with other chemotherapeutics to treat carcinoma, inhibit FUBP1 activity...
October 12, 2017: Biochemical Pharmacology
Kazuko Okamoto-Shibayama, Jin Sekino, Kouki Yoshikawa, Atsushi Saito, Kazuyuki Ishihara
Treponemes occur in the microflora of the dental plaque. Certain Treponema species that are frequently isolated from chronic periodontitis lesions are involved in its initiation and progression. In addition to mechanical instrumentation, antimicrobial agents are used as an adjunctive treatment modality for periodontitis. Despite its importance for successful antimicrobial treatment, information about susceptibility is limited for Treponema species. The aim of this study was to assess the susceptibility of two Treponema denticola strains, Treponema socranskii, and Treponema vincentii to eleven antimicrobial agents...
October 10, 2017: Anaerobe
D-P Wu, X-B Yan, L-G Liu, C Tian, K Han, H Zhang, D-L Min
OBJECTIVE: Topoisomerase IIβ binding protein 1 (TopBP1) is involved in DNA damage and replication checkpoint and has been shown to be related to tumorigenesis in many cancer types. This study aimed to evaluate the biological role and clinicopathological significance of TopBP1 in OS. PATIENTS AND METHODS: TopBP1 expression in sarcoma patients was determined through the Oncomine database, and the prognostic role of TopBP1 expression was assessed in a retrospective cohort study...
September 2017: European Review for Medical and Pharmacological Sciences
Ilaria Dalla Rosa, Hongliang Zhang, Salim Khiati, Xiaolin Wu, Yves Pommier
Mitochondrial DNA (mtDNA) is essential for cell viability because it encodes subunits of the respiratory chain complexes. Mitochondrial topoisomerase IB (TOP1MT) facilitates mtDNA replication by removing DNA topological tensions produced during mtDNA transcription, but appears to be dispensable. To test whether cells lacking TOP1MT have aberrant mtDNA transcription, we performed mitochondrial transcriptome profiling. To that end, we designed and implemented a customized tiling array, which enabled genome-wide, strand-specific, and simultaneous detection of all mitochondrial transcripts...
October 11, 2017: Journal of Biological Chemistry
Thais Rohde Pavan, Markus Bredemeier, Vanessa Hax, Karina Gatz Capobianco, Rafael da Silva Mendonça Chakr, Ricardo Machado Xavier
The objective of this study is to test the association of the severity of nailfold capillaroscopy (NFC) abnormalities with mortality in systemic sclerosis (SSc). One hundred and seventy SSc patients underwent an extensive evaluation (including high-resolution computed tomography, pulmonary function tests, and Doppler echocardiography) at baseline following a standard protocol. Capillary loss on NFC was evaluated using the avascular score (AS, ranging from 0 to 3), and the mean number of ectasias, megacapillaries, and hemorrhages per finger was also recorded...
October 10, 2017: Clinical Rheumatology
Tyler Li, Juanjuan Guo, Hao Zhang
Topoisomerase IV is an enzyme that is mainly responsible for unwinding interlocked DNA strands at the final stage of prokaryotic DNA replication. Due to its exclusivity in prokaryotes, topoisomerase IV has been identified as a validated target for quinolone-based antibiotics in the past years for treating bacterial infection. In consideration that bacterial resistance to such antibiotics has occurred constantly, several newly designed pseudosubstrate oligonucleotides as DNA topoisomerase IV inhibitors have been examined during our recent investigations...
September 28, 2017: Bioorganic & Medicinal Chemistry Letters
Hong Jin, Chao Qi, Yanping Zou, Yingying Kong, Zhi Ruan, Honghui Ding, Xinyou Xie, Jun Zhang
PURPOSE: This study aims to investigate the synergistic antimicrobial activity of four phytoalexins in combination with fluoroquinolones against Ureaplasma spp., a genus of cell wall-free bacteria that are intrinsically resistant to many available antibiotics, making treatment inherently difficult. METHODOLOGY: A total of 22 958 urogenital tract specimens were assessed for Ureaplasma spp. identification and antimicrobial susceptibility. From these, 31 epidemiologically unrelated strains were randomly selected for antimicrobial susceptibility testing to determine the minimum inhibitory concentration (MIC) of four fluoroquinolones and the corresponding quinolone resistance-determining regions (QRDRs)...
October 6, 2017: Journal of Medical Microbiology
Agnieszka Strzalka, Marcin J Szafran, Terence Strick, Dagmara Jakimowicz
Streptomyces topoisomerase I (TopA) exhibits exceptionally high processivity. The enzyme, as other actinobacterial topoisomerases I, differs from its bacterial homologs in its C-terminal domain (CTD). Here, bioinformatics analyses established that the presence of lysine repeats is a characteristic feature of actinobacterial TopA CTDs. Streptomyces TopA contains the longest stretch of lysine repeats, which terminate with acidic amino acids. DNA-binding studies revealed that the lysine repeats stabilized the TopA-DNA complex, while single-molecule experiments showed that their elimination impaired enzyme processivity...
September 13, 2017: Nucleic Acids Research
Mark A Miles, Christine J Hawkins
Chemotherapy drugs interfere with cellular processes to generate genotoxic lesions that activate cell death pathways. Sustained DNA damage induced by these drugs can provoke mutations in surviving non-cancerous cells, potentially increasing the risk of therapy-related cancers. Ligation of death receptors by ligands such as TRAIL, and subsequent activation of extrinsic apoptotic pathways, also provokes mutations. In this study, we show that executioner caspase activation of the apoptotic nuclease CAD/DFF40 is essential for TRAIL-induced mutations in surviving cells...
October 5, 2017: Cell Death & Disease
Nerea Iniesta Arandia, Carmen Pilar Simeón-Aznar, Alfredo Guillén Del Castillo, Dolores Colunga Argüelles, Manuel Rubio-Rivas, Luis Trapiella Martínez, Francisco José García Hernández, Luis Sáez Comet, María Victoria Egurbide Arberas, Norberto Ortego-Centeno, Mayka Freire, Begoña Marí Alfonso, José Antonio Vargas Hitos, Juan José Ríos Blanco, José Antonio Todolí Parra, Monica Rodríguez-Carballeira, Adela Marín Ballvé, Antonio Javier Chamorro Fernández, Xavier Pla Salas, Ana Belen Madroñero Vuelta, Manuel Ruiz Muñoz, Vicent Fonollosa Pla, Gerard Espinosa
OBJECTIVES: To assess the clinical manifestations and prognosis of Spanish patients with systemic sclerosis (SSc) according to their immunological profile. METHODS: From the Spanish Scleroderma Study Group or RESCLE (Registro de ESCLErodermia as Spanish nomenclature) Registry we selected those patients in which anti-centromere (ACA), anti-topoisomerase I (ATA), and anti-RNA polymerase III (ARA) antibodies had been determined, and a single positivity for each SSc specific antibody was detected...
September 21, 2017: Clinical and Experimental Rheumatology
Ganesha P Pitchai, Manuel Kaulich, Anna H Bizard, Pablo Mesa, Qi Yao, Kata Sarlos, Werner W Streicher, Erich A Nigg, Guillermo Montoya, Ian D Hickson
PICH is a DNA translocase required for the maintenance of chromosome stability in human cells. Recent data indicate that PICH co-operates with topoisomerase IIα to suppress pathological chromosome missegregation through promoting the resolution of ultra-fine anaphase bridges (UFBs). Here, we identify the BEN domain-containing protein 3 (BEND3) as an interaction partner of PICH in human cells in mitosis. We have purified full length PICH and BEND3 and shown that they exhibit a functional biochemical interaction in vitro...
September 5, 2017: Nucleic Acids Research
Ying-Ren Wang, Shin-Fu Chen, Chyuan-Chuan Wu, Yi-Wen Liao, Te-Sheng Lin, Ko-Ting Liu, Yi-Song Chen, Tsai-Kun Li, Tun-Cheng Chien, Nei-Li Chan
Human type II topoisomerase (Top2) isoforms, hTop2α and hTop2β, are targeted by some of the most successful anticancer drugs. These drugs induce Top2-mediated DNA cleavage to trigger cell-death pathways. The potency of these drugs correlates positively with their efficacy in stabilizing the enzyme-mediated DNA breaks. Structural analysis of hTop2α and hTop2β revealed the presence of methionine residues in the drug-binding pocket, we therefore tested whether a tighter Top2-drug association may be accomplished by introducing a methionine-reactive Pt2+ into a drug to further stabilize the DNA break...
August 24, 2017: Nucleic Acids Research
Wen Shen, Hong Sun, Cheryl L De Hoyos, Jeffrey K Bailey, Xue-Hai Liang, Stanley T Crooke
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...
August 9, 2017: Nucleic Acids Research
Ying-Ren Wang, Shin-Fu Chen, Chyuan-Chuan Wu, Yi-Wen Liao, Te-Sheng Lin, Ko-Ting Liu, Yi-Song Chen, Tsai-Kun Li, Tun-Cheng Chien, Nei-Li Chan
No abstract text is available yet for this article.
September 4, 2017: Nucleic Acids Research
Geneviève Pépin, Charlotte Nejad, Jonathan Ferrand, Belinda J Thomas, H James Stunden, Elaine Sanij, Chwan-Hong Foo, Cameron R Stewart, Jason E Cain, Philip G Bardin, Bryan R G Williams, Michael P Gantier
Inflammatory responses, while essential for pathogen clearance, can also be deleterious to the host. Chemical inhibition of topoisomerase 1 (Top1) by low-dose camptothecin (CPT) can suppress transcriptional induction of antiviral and inflammatory genes and protect animals from excessive and damaging inflammatory responses. We describe the unexpected finding that minor DNA damage from topoisomerase 1 inhibition with low-dose CPT can trigger a strong antiviral immune response through cyclic GMP-AMP synthase (cGAS) detection of cytoplasmic DNA...
October 3, 2017: MBio
Pawadee Lohavanichbutr, Lori C Sakoda, Christopher I Amos, Susanne M Arnold, David C Christiani, Michael P A Davies, John K Field, Eric B Haura, Rayjean J Hung, Takashi Kohno, Maria Teresa Landi, Geoffrey Liu, Yi Liu, Michael W Marcus, Grainne M O'Kane, Matthew B Schabath, Kouya Shiraishi, Stacey A Slone, Adonina Tardon, Ping Yang, Kazushi Yoshida, Ruyang Zhang, Xuchen Zong, Gary G Goodman, Noel S Weiss, Chu Chen
PURPOSE: DNA topoisomerase inhibitors are commonly used for treating small cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single nucleotide polymorphisms (SNPs) are associated with overall survival among SCLC patients. EXPERIMENTAL DESIGN: Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO)...
October 3, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Fabrizio Benedetti, Dusan Racko, Julien Dorier, Yannis Burnier, Andrzej Stasiak
The question of how self-interacting chromatin domains in interphase chromosomes are structured and generated dominates current discussions on eukaryotic chromosomes. Numerical simulations using standard polymer models have been helpful in testing the validity of various models of chromosome organization. Experimental contact maps can be compared with simulated contact maps and thus verify how good is the model. With increasing resolution of experimental contact maps, it became apparent though that active processes need to be introduced into models to recapitulate the experimental data...
September 29, 2017: Nucleic Acids Research
Valeria Visone, Wenyuan Han, Giuseppe Perugino, Giovanni Del Monaco, Qunxin She, Mosè Rossi, Anna Valenti, Maria Ciaramella
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...
2017: PloS One
Alberto Ballestrero, Davide Bedognetti, Domenico Ferraioli, Paola Franceschelli, Sana Intidhar Labidi-Galy, Elisabetta Leo, Junko Murai, Yves Pommier, Petros Tsantoulis, Valerio Gaetano Vellone, Gabriele Zoppoli
SLFN11 is a recently discovered protein with a putative DNA/RNA helicase function. First identified in association with the maturation of thymocytes, SLFN11 was later causally associated, by two independent groups, with the resistance to DNA damaging agents such as topoisomerase I and II inhibitors, platinum compounds, and other alkylators, making it an attractive molecule for biomarker development. Later, SLFN11 was linked to antiviral response in human cells and interferon production, establishing a potential bond between immunity and chemotherapy...
October 2, 2017: Journal of Translational Medicine
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