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Peter A Henriksen
Anthracycline chemotherapy causes dose-related cardiomyocyte injury and death leading to left ventricular dysfunction. Clinical heart failure may ensue in up to 5% of high-risk patients. Improved cancer survival together with better awareness of the late effects of cardiotoxicity has led to growing recognition of the need for surveillance of anthracycline-treated cancer survivors with early intervention to treat or prevent heart failure. The main mechanism of anthracycline cardiotoxicity is now thought to be through inhibition of topoisomerase 2β resulting in activation of cell death pathways and inhibition of mitochondrial biogenesis...
December 7, 2017: Heart: Official Journal of the British Cardiac Society
Ajinkya S Kawale, Lawrence F Povirk
Tyrosyl-DNA Phosphodiesterases 1 (TDP1) and 2 (TDP2) are eukaryotic enzymes that clean-up after aberrant topoisomerase activity. While TDP1 hydrolyzes phosphotyrosyl peptides emanating from trapped topoisomerase I (Top I) from the 3' DNA ends, topoisomerase 2 (Top II)-induced 5'-phosphotyrosyl residues are processed by TDP2. Even though the canonical functions of TDP1 and TDP2 are complementary, they exhibit little structural or sequence similarity. Homozygous mutations in genes encoding these enzymes lead to the development of severe neurodegenerative conditions due to the accumulation of transcription-dependent topoisomerase cleavage complexes underscoring the biological significance of these enzymes in the repair of topoisomerase-DNA lesions in the nervous system...
December 4, 2017: Nucleic Acids Research
Chada Raji Reddy, Kathe Mallesh
An efficient protocol for the synthesis of diversely substituted 7-hydroxyisoindolo[2,1-b]isoquinolin-5(7H)-ones from the reaction of N-(pivaloyloxy)benzamides with 2-alkynyl aldehydes has been developed, which proceeds through sequential alkyne insertion followed by addition of the amide nitrogen on to the aldehyde. This method provided the products with aminal functionality as a handle for further diversification. The synthetic utility of this strategy was successfully illustrated by the concise, two-step synthesis of an alkaloid, rosettacin, and a topoisomerase I inhibitor...
December 7, 2017: Organic Letters
Ainhoa Mariezcurrena, Frank Uhlmann
DNA replication of circular genomes generates physically interlinked or catenated sister DNAs. These are resolved through transient DNA fracture by type II topoisomerases to permit chromosome segregation during cell division. Topoisomerase II is similarly required for linear chromosome segregation, suggesting that linear chromosomes also remain intertwined following DNA replication. Indeed, chromosome resolution defects are a frequent cause of chromosome segregation failure and consequent aneuploidies. When and where intertwines arise and persist along linear chromosomes are not known, owing to the difficulty of demonstrating intertwining of linear DNAs...
December 5, 2017: Genes & Development
S Yilmaz, I Yalcin, S Okten, F K Onurdag, E Aki-Yalcin
Acinetobacter baumannii has emerged as an important pathogen for nosocomial infections having high morbidity and mortality. This pathogen is notorious for antimicrobial resistance to many common antimicrobial agents including fluoroquinolones, which have both intrinsic and acquired resistance mechanisms. Fluoroquinolones targeting the bacterial topoisomerase II (DNA gyrase and Topo IV) show potent broad-spectrum antibacterial activity by the stabilization of the covalent enzyme-DNA complex. However, their efficacy is now being threatened by an increasing prevalence of resistance...
November 2017: SAR and QSAR in Environmental Research
Martina Durcik, Päivi Tammela, Michaela Barančoková, Tihomir Tomašič, Janez Ilaš, Danijel Kikelj, Nace Zidar
ATP-competitive inhibitors of DNA gyrase and topoisomerase IV (topo IV) are among the most interesting classes of antibacterial drugs that do not have any representative in the antibacterial pipeline. We have developed thirty-two new N-phenylpyrrolamides and evaluated them against DNA gyrase and topoisomerase IV from Escherichia coli and Staphylococcus aureus. Antibacterial activities were studied against Gram-positive and Gram-negative bacterial strains. The most potent compound displayed an IC50 of 47 nM against E...
December 5, 2017: ChemMedChem
Toshiyuki Nanbu, Naoki Umemura, Emika Ohkoshi, Kumi Nanbu, Hiroshi Sakagami, Jun Shimada
The aim of the present study was to search for an effective regimen among existing chemotherapies for head and neck squamous cell carcinoma (HNSCC). Among the tested drugs, we focused on combined SN-38, which is the active metabolite produced from irinotecan hydrochloride - a type I DNA topoisomerase inhibitor - after it is metabolized by carboxylesterase in the liver and gefitinib, an EGFR tyrosine kinase inhibitor treatment, based on the ability of this combination to inhibit HNSCC cell growth. Contrary to our expectation, in vivo, there was no significant difference in tumor growth suppression between gefitinib-only treatment and gefitinib plus SN-38...
January 2018: Oncology Reports
Khaled Abdellatif, Mostafa M Elbadawi, Mohammed T Elsaady, Amer Ali Abd El-Hafeez, Takashi Fujimura, Seiji Kawamoto, Ahmed I Khodair
Background Some 2-thioxoimidazolidinones have been reported as anti-prostate and anti-breast cancer agents through their inhibitory activity on topoisomerase I that is considered as a potential chemotherapeutic target. Objective A new series of 3,5-disubstituted-2-thioxoimidazolidinone derivatives 10a-f and their S-methyl analogs 11a-f were designed, synthesized and evaluated for cytotoxicity against human prostate cancer cell line (PC-3), human breast cancer cell line (MCF-7) and non-cancerous human lung fibroblast cell line (WI-38)...
November 29, 2017: Anti-cancer Agents in Medicinal Chemistry
Xiaomei Li, Xingkang Wu, Jing Zhu, Yuemao Shen
Ten new pentangular polyphenols, namely amexanthomycins A-J (1-10) were isolated from the strain Amycolatopsis mediterranei S699∆rifA constructed by deleting the polyketide synthase genes responsible for the biosynthesis of rifamycins. Their structures were elucidated on the basis of 1D and 2D NMR spectroscopic data and high-resolution ESIMS. Amexanthomycins A-C (1-3) showed inhibitory activity against human DNA topoisomerases.
November 27, 2017: Applied Microbiology and Biotechnology
Andrei Kuzminov
Head-on replication-transcription conflict is especially bitter in bacterial chromosomes, explaining why actively transcribed genes are always co-oriented with replication. The mechanism of this conflict remains unclear, besides the anticipated accumulation of positive supercoils between head-on-conflicting polymerases. Unexpectedly, experiments in bacterial and human cells reveal that head-on replication-transcription conflict induces R-loops, indicating hypernegative supercoiling [(-)sc] in the region - precisely the opposite of that assumed...
November 24, 2017: Trends in Genetics: TIG
Albert J Erives
BACKGROUND: While the genomes of eukaryotes and Archaea both encode the histone-fold domain, only eukaryotes encode the core histone paralogs H2A, H2B, H3, and H4. With DNA, these core histones assemble into the nucleosomal octamer underlying eukaryotic chromatin. Importantly, core histones for H2A and H3 are maintained as neofunctionalized paralogs adapted for general bulk chromatin (canonical H2 and H3) or specialized chromatin (H2A.Z enriched at gene promoters and cenH3s enriched at centromeres)...
November 28, 2017: Epigenetics & Chromatin
Walaa A El-Kashak, Samir M Osman, Ahmed H Gaara, Sayed A El-Toumy, Tahia K Mohamed, Iñaki Brouard
CONTEXT: Terminalia muelleri Benth. (Combretaceae), is rich with phenolics that have antioxidant and cytotoxic activities. No screening studies were published before on T. muelleri. OBJECTIVE: The study focused on isolation and identification of secondary metabolites from aqueous methanol leaf extract of T. muelleri and evaluation of its biological activities. MATERIALS AND METHODS: The n-butanol extract was chromatographed on polyamide 6, and eluted with H2O/MeOH mixtures of decreasing polarity, then separated by different chromatographic tools that yielded 10 phenolic compounds...
December 2017: Pharmaceutical Biology
Shohei Miyata, Li-Yan Wang, Susumu Kitanaka
Acute lymphoblastic leukemia (ALL) samples exhibit an activated PI3K/Akt pathway, which suggests a general role of Akt in the development of leukemia. We have previously used western blot analysis to show that the catalytic topoisomerase (topo) inhibitor, 3EZ, 20Ac-ingenol, induced DNA damage response (DDR), which activated ATR, downregulated p-Akt through upregulation of PTEN level, and led to cell cycle arrest or apoptosis. In this study, we used ATR or PTEN siRNA and observed that the specific cell arrest and apoptosis of BALL-1 cells in DDR caused by 3EZ, 20Ac-ingenol was dependant on activation of ATR and downregulation of nuclear p-Akt through upregulation of PTEN...
August 24, 2017: Leukemia Research
Philippe Pasero, Alessandro Vindigni
In a lifetime, a human being synthesizes approximately 2×1016 meters of DNA, a distance that corresponds to 130,000 times the distance between the Earth and the Sun. This daunting task is executed by thousands of replication forks, which progress along the chromosomes and frequently stall when they encounter DNA lesions, unusual DNA structures, RNA polymerases, or tightly-bound protein complexes. To complete DNA synthesis before the onset of mitosis, eukaryotic cells have evolved complex mechanisms to process and restart arrested forks through the coordinated action of multiple nucleases, topoisomerases, and helicases...
November 27, 2017: Annual Review of Genetics
Ian G Cowell, Caroline A Austin
The TARDIS assay was originally developed as a means of detecting and quantifying melphalan and cisplatin DNA adducts at the single cell level, but it has since been adapted to quantify topoisomerase DNA complexes that result from the actions of topoisomerase poisons and this is currently the main use of the assay. The method employs sensitive immunofluorescent detection to quantify topoisomerase molecules covalently coupled to DNA in what are often referred to as cleavage complexes. Free topoisomerase molecules, and other cellular constituents are first removed using salt-detergent extraction of agarose-embedded, unfixed cells...
2018: Methods in Molecular Biology
Jay Anand, Yilun Sun, Yang Zhao, Karin C Nitiss, John L Nitiss
DNA topoisomerases carry out topological transformations of DNA by introducing transient DNA breaks. The covalent intermediate of topoisomerase reactions include the topoisomerase protein covalently bound to DNA by a phosphotyrosine intermediate. Anti-cancer drugs that target topoisomerases typically trap the covalent intermediate, and generate cytotoxic enzyme dependent DNA damage. More recently, structural alterations in DNA such as DNA damage have also been shown to trap covalent intermediates of topoisomerase reactions...
2018: Methods in Molecular Biology
Gan Luan, Karl Drlica
The quinolones are potent antibacterials that act by forming complexes with DNA and either gyrase or topoisomerase IV. These ternary complexes, called cleaved complexes because the DNA moiety is broken, block replication, transcription, and bacterial growth. Cleaved complexes readily form in vitro when gyrase, plasmid DNA, and quinolone are combined and incubated; complexes are detected by the linearization of plasmid DNA, generally assayed by gel electrophoresis. The stability of the complexes can be assessed by treatment with EDTA, high temperature, or dilution to dissociate the complexes and reseal the DNA moiety...
2018: Methods in Molecular Biology
Thirunavukkarasu Annamalai, Bokun Cheng, Neelam Keswani, Yuk-Ching Tse-Dinh
Bacterial Topoisomerase I is a potential target for the identification of novel topoisomerase poison inhibitors that could provide leads for a new class of antibacterial compounds. Here we describe in detail a fluorescence-based cleavage assay that is successfully used in HTS for the discovery of bacterial topoisomerase Ι poisons.
2018: Methods in Molecular Biology
Jessica S Williams, Thomas A Kunkel
Ribonucleotides incorporated into DNA by the DNA polymerases can be incised by Topoisomerase 1 (Top1) to initiate removal of ribonucleotides from the genome. This Top1-dependent ribonucleotide removal has been demonstrated to result in multiple forms of genome instability in yeast. Here, we describe both quantitative and qualitative assays to identify mutations and other forms of DNA damage resulting from Top1-cleavage at unrepaired genomic ribonucleotides.
2018: Methods in Molecular Biology
Katherine Furniss, Amit C J Vas, Andrew B Lane, Duncan J Clarke
Topoisomerase II activity is crucial to maintain genome stability through the removal of catenanes in the DNA formed during DNA replication and scaffolding the mitotic chromosome. Perturbed Topo II activity causes defects in chromosome segregation due to persistent catenations and aberrant DNA condensation during mitosis. Recently, novel top2 alleles in the yeast Saccharomyces cerevisiae revealed a checkpoint control which responds to perturbed Topo II activity. Described in this chapter are protocols for assaying the phenotypes seen in top2 mutants on a cell biological basis in live cells: activation of the Topo II checkpoint using spindle morphology, chromosome condensation using fluorescently labeled chromosomal loci and cell cycle progression by flow cytometry...
2018: Methods in Molecular Biology
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