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https://www.readbyqxmd.com/read/28697309/identification-of-natural-products-that-inhibit-the-catalytic-function-of-human-tyrosyl-dna-phosphodiesterase-tdp1
#1
Alun Bermingham, Edmund Price, Christophe Marchand, Adel Chergui, Alena Naumova, Emily L Whitson, Lauren R H Krumpe, Ekaterina I Goncharova, Jason R Evans, Tawnya C McKee, Curtis J Henrich, Yves Pommier, Barry R O'Keefe
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme crucial for cleavage of the covalent topoisomerase 1-DNA complex, an intermediate in DNA repair. TDP1 plays a role in reversing inhibition of topoisomerase I by camptothecins, a series of potent and effective inhibitors used in the treatment of colorectal, ovarian, and small-cell lung cancers. It is hypothesized that inhibition of TDP1 activity may enhance camptothecin sensitivity in tumors. Here, we describe the design, development, and execution of a novel assay to identify inhibitors of TDP1 present in natural product extracts...
July 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28657311/design-and-synthesis-of-chlorinated-and-fluorinated-7-azaindenoisoquinolines-as-potent-cytotoxic-anticancer-agents-that-inhibit-topoisomerase-i
#2
Mohamed S A Elsayed, Yafan Su, Ping Wang, Taresh Sethi, Keli Agama, Azhar Ravji, Christophe E Redon, Evgeny Kiselev, Katharine A Horzmann, Jennifer L Freeman, Yves Pommier, Mark Cushman
The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model. Some of the new Top1 inhibitors also possess moderate inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2), two enzymes that are involved in DNA damage repair resulting from Top1 inhibitors, and they produce significantly more DNA damage in cancer cells than in normal cells...
June 28, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28550017/a-lysine-desert-protects-a-novel-domain-in-the-slx5-slx8-sumo-targeted-ub-ligase-to-maintain-sumoylation-levels-in-saccharomyces-cerevisiae
#3
Pragati Sharma, Janet R Mullen, Minxing Li, Mikel Zaratiegui, Samuel F Bunting, Steven J Brill
Protein modification by the small ubiquitin-like modifier (SUMO) plays important roles in genome maintenance. In Saccharomyces cerevisiae, proper regulation of sumoylation is known to be essential for viability in certain DNA repair mutants. Here we find the opposite result; proper regulation of sumoylation is lethal in certain DNA repair mutants. Yeast cells lacking the repair factors TDP1 and WSS1 are synthetically lethal due to their redundant roles in removing Top1-DNA covalent complexes (Top1ccs). A screen for suppressors of tdp1∆ wss1∆ synthetic lethality isolated mutations in genes known to control global sumoylation levels including ULP1, ULP2, SIZ2 and SLX5 The results suggest that alternative pathways of repair become available when sumoylation levels are altered...
May 26, 2017: Genetics
https://www.readbyqxmd.com/read/28508041/mitochondrial-protein-linked-dna-breaks-perturb-mitochondrial-gene-transcription-and-trigger-free-radical-induced-dna-damage
#4
Shih-Chieh Chiang, Martin Meagher, Nick Kassouf, Majid Hafezparast, Peter J McKinnon, Rachel Haywood, Sherif F El-Khamisy
Breakage of one strand of DNA is the most common form of DNA damage. Most damaged DNA termini require end-processing in preparation for ligation. The importance of this step is highlighted by the association of defects in the 3'-end processing enzyme tyrosyl DNA phosphodiesterase 1 (TDP1) and neurodegeneration and by the cytotoxic induction of protein-linked DNA breaks (PDBs) and oxidized nucleic acid intermediates during chemotherapy and radiotherapy. Although much is known about the repair of PDBs in the nucleus, little is known about this process in the mitochondria...
April 2017: Science Advances
https://www.readbyqxmd.com/read/28418653/synthesis-and-biological-evaluation-of-the-first-triple-inhibitors-of-human-topoisomerase-1-tyrosyl-dna-phosphodiesterase-1-tdp1-and-tyrosyl-dna-phosphodiesterase-2-tdp2
#5
Ping Wang, Mohamed S A Elsayed, Caroline B Plescia, Azhar Ravji, Christophe E Redon, Evgeny Kiselev, Christophe Marchand, Olga Zeleznik, Keli Agama, Yves Pommier, Mark Cushman
Tdp1 and Tdp2 are two tyrosyl-DNA phosphodiesterases that can repair damaged DNA resulting from topoisomerase inhibitors and a variety of other DNA-damaging agents. Both Tdp1 and Tdp2 inhibition could hypothetically potentiate the cytotoxicities of topoisomerase inhibitors. This study reports the successful structure-based design and synthesis of new 7-azaindenoisoquinolines that act as triple inhibitors of Top1, Tdp1, and Tdp2. Enzyme inhibitory data and cytotoxicity data from human cancer cell cultures establish that modification of the lactam side chain of the 7-azaindenoisoquinolines can modulate their inhibitory potencies and selectivities vs Top1, Tdp1, and Tdp2...
April 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28372328/blood-based-oligomeric-and-other-protein-variant-biomarkers-to-facilitate-pre-symptomatic-diagnosis-and-staging-of-alzheimer-s-disease
#6
Stephanie M Williams, Philip Schulz, Terrone L Rosenberry, Richard J Caselli, Michael R Sierks
Oligomeric forms of amyloid-β (Aβ), tau, and TDP-43 play important roles in Alzheimer's disease (AD), and therefore are promising biomarkers. We previously generated single chain antibody fragments (scFvs) that selectively bind disease-related variants of these proteins including A4, C6T, and E1, which bind different oligomeric Aβ variants; D11C, which binds oligomeric tau; and AD-TDP1 and AD-TDP2, which bind disease related TDP-43 variants. To determine the utility of these disease-related variants as early biomarkers, we first analyzed 11 human sera samples obtained ∼2 years prior to an initial mild cognitive impairment (MCI) diagnosis...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28182794/identification-of-several-high-risk-hpv-inhibitors-and-drug-targets-with-a-novel-high-throughput-screening-assay
#7
Mart Toots, Mart Ustav, Andres Männik, Karl Mumm, Kaido Tämm, Tarmo Tamm, Ene Ustav, Mart Ustav
Human papillomaviruses (HPVs) are oncogenic viruses that cause numerous different cancers as well as benign lesions in the epithelia. To date, there is no effective cure for an ongoing HPV infection. Here, we describe the generation process of a platform for the development of anti-HPV drugs. This system consists of engineered full-length HPV genomes that express reporter genes for evaluation of the viral copy number in all three HPV replication stages. We demonstrate the usefulness of this system by conducting high-throughput screens to identify novel high-risk HPV-specific inhibitors...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28120709/dna-damaging-anticancer-drugs-a-perspective-for-dna-repair-oriented-therapy
#8
Janusz Blasiak
DNA-damaging drugs in cancer present two main problems: therapeutic resistance and side effects and both can associate with DNA repair, which can be targeted in cancer therapy. Bleomycin (BLM) induces complex DNA damages, including strand breaks, base loss and 3'-phosphoglycolate (3'PG) residues repaired by several pathways, but 3'PGs must be processed to the 3'-OH ends, usually by tyrosyl-DNA phosphodiesterase 1 (Tdp1). Therefore, targeting Tdp1 can improve anticancer therapy with BLM. Mitomycin C (MMC) produces a variety of adducts with DNA, including inter-strand cross-links (ICLs) and Xeroderma pigmentosum (XP) proteins, including XPG, XPE and XPF can be crucial for the initial stage of ICL repair, so they can be targeted by inhibitors to increase toxicity of MMC in cancer cells...
January 24, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27943678/cytotoxicity-of-tirapazamine-3-amino-1-2-4-benzotriazine-1-4-dioxide-induced-dna-damage-in-chicken-dt40-cells
#9
Takahito Moriwaki, Saki Okamoto, Hiroyuki Sasanuma, Hideko Nagasawa, Shunichi Takeda, Shin-Ichiro Masunaga, Keizo Tano
Tirapazamine (TPZ) is an anticancer drug with highly selective cytotoxicity toward hypoxic cells. TPZ is converted to a radical intermediate under hypoxic conditions, and this intermediate interacts with intracellular macromolecules, including DNA. TPZ has been reported to indirectly induce DNA double-strand breaks (DSBs) through the formation of various intermediate DNA lesions under hypoxic conditions. Although the topoisomerase II-DNA complex has been identified as one of these intermediates, other lesions have not yet been defined...
February 20, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27933897/tyrosyl-dna-phosphodiesterase-1-inhibitors-usnic-acid-enamines-enhance-the-cytotoxic-effect-of-camptothecin
#10
Alexandra Zakharenko, Olga Luzina, Olga Koval, Dmitry Nilov, Irina Gushchina, Nadezhda Dyrkheeva, Vytas Švedas, Nariman Salakhutdinov, Olga Lavrik
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a repair enzyme for stalled DNA-topoisomerase 1 (Top1) cleavage complexes and other 3'-end DNA lesions. TDP1 is a perspective target for anticancer therapy based on Top1-poison-mediated DNA damage. Several novel usnic acid derivatives with an enamine moiety have been synthesized and tested as inhibitors of TDP1. The enamines of usnic acid showed IC50 values in the range of 0.16 to 2.0 μM. These compounds revealed moderate cytotoxicity against human tumor MCF-7 cells...
November 23, 2016: Journal of Natural Products
https://www.readbyqxmd.com/read/27893431/dysregulated-human-tyrosyl-dna-phosphodiesterase-i-acts-as-cellular-toxin
#11
Selma M Cuya, Evan Q Comeaux, Keith Wanzeck, Karina J Yoon, Robert C A M van Waardenburg
Tyrosyl-DNA phosphodiesterase I (TDP1) hydrolyzes the drug-stabilized 3'phospho-tyrosyl bond formed between DNA topoisomerase I (TOPO1) and DNA. TDP1-mediated hydrolysis uses a nucleophilic histidine (Hisnuc) and a general acid/base histidine (Hisgab). A Tdp1Hisgab to Arg mutant identified in patients with the autosomal recessive neurodegenerative disease SCAN1 causes stabilization of the TDP1-DNA intermediate. Based on our previously reported Hisgab-substitutions inducing yeast toxicity (Gajewski et al. J...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27789688/epigenetic-changes-in-histone-acetylation-underpin-resistance-to-the-topoisomerase-i-inhibitor-irinotecan
#12
Cornelia Meisenberg, Mohamed E Ashour, Lamia El-Shafie, Chunyan Liao, Adam Hodgson, Alice Pilborough, Syed A Khurram, Jessica A Downs, Simon E Ward, Sherif F El-Khamisy
The topoisomerase I (TOP1) inhibitor irinotecan triggers cell death by trapping TOP1 on DNA, generating cytotoxic protein-linked DNA breaks (PDBs). Despite its wide application in a variety of solid tumors, the mechanisms of cancer cell resistance to irinotecan remains poorly understood. Here, we generated colorectal cancer (CRC) cell models for irinotecan resistance and report that resistance is neither due to downregulation of the main cellular target of irinotecan TOP1 nor upregulation of the key TOP1 PDB repair factor TDP1...
October 26, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27747316/tyrosyl-dna-phosphodiesterase-i-a-critical-survival-factor-for-neuronal-development-and-homeostasis
#13
Robert C A M van Waardenburg
Tyrosyl-DNA phosphodiesterase I (TDP1), like most DNA repair associated proteins, is not essential for cell viability. However, dysfunctioning TDP1 or ATM (ataxia telangiectasia mutated) results in autosomal recessive neuropathology with similar phenotypes, including cerebellar atrophy. Dual inactivation of TDP1 and ATM causes synthetic lethality. A TDP1H(493)R catalytic mutant is associated with spinocerebellar ataxia with axonal neuropathy (SCAN1), and stabilizes the TDP1 catalytic obligatory enzyme-DNA covalent complex...
2016: Journal of Neurology & Neuromedicine
https://www.readbyqxmd.com/read/27687298/pre-steady-state-kinetics-of-dna-binding-and-abasic-site-hydrolysis-by-tyrosyl-dna-phosphodiesterase-1
#14
Nikita A Kuznetsov, Natalia A Lebedeva, Alexandra A Kuznetsova, Nadejda I Rechkunova, Nadezhda S Dyrkheeva, Maxim S Kupryushkin, Dmitry A Stetsenko, Dmitrii V Pyshnyi, Olga S Fedorova, Olga I Lavrik
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) processes DNA 3'-end-blocking modifications, possesses DNA and RNA 3'-nucleosidase activity and is also able to hydrolyze an internal apurinic/apyrimidinic (AP) site and its synthetic analogs. The mechanism of Tdp1 interaction with DNA was analyzed using pre-steady state stopped-flow kinetics with tryptophan, 2-aminopurine and Förster resonance energy transfer fluorescence detection. Phosphorothioate or tetramethyl phosphoryl guanidine groups at the 3'-end of DNA have been used to prevent 3'-nucleosidase digestion by Tdp1...
August 16, 2016: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/27649880/roles-of-eukaryotic-topoisomerases-in-transcription-replication-and-genomic-stability
#15
REVIEW
Yves Pommier, Yilun Sun, Shar-Yin N Huang, John L Nitiss
Topoisomerases introduce transient DNA breaks to relax supercoiled DNA, remove catenanes and enable chromosome segregation. Human cells encode six topoisomerases (TOP1, TOP1mt, TOP2α, TOP2β, TOP3α and TOP3β), which act on a broad range of DNA and RNA substrates at the nuclear and mitochondrial genomes. Their catalytic intermediates, the topoisomerase cleavage complexes (TOPcc), are therapeutic targets of various anticancer drugs. TOPcc can also form on damaged DNA during replication and transcription, and engage specific repair pathways, such as those mediated by tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2 and by endonucleases (MRE11, XPF-ERCC1 and MUS81)...
November 2016: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/27551064/overexpression-screens-identify-conserved-dosage-chromosome-instability-genes-in-yeast-and-human-cancer
#16
Supipi Duffy, Hok Khim Fam, Yi Kan Wang, Erin B Styles, Jung-Hyun Kim, J Sidney Ang, Tejomayee Singh, Vladimir Larionov, Sohrab P Shah, Brenda Andrews, Cornelius F Boerkoel, Philip Hieter
Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells...
September 6, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27470939/neurological-disorders-associated-with-dna-strand-break-processing-enzymes
#17
REVIEW
Bingcheng Jiang, J N Mark Glover, Michael Weinfeld
The termini of DNA strand breaks induced by reactive oxygen species or by abortive DNA metabolic intermediates require processing to enable subsequent gap filling and ligation to proceed. The three proteins, tyrosyl DNA-phosphodiesterase 1 (TDP1), aprataxin (APTX) and polynucleotide kinase/phosphatase (PNKP) each act on a discrete set of modified strand-break termini. Recently, a series of neurodegenerative and neurodevelopmental disorders have been associated with mutations in the genes coding for these proteins...
January 2017: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/27262532/end-processing-nucleases-and-phosphodiesterases-an-elite-supporting-cast-for-the-non-homologous-end-joining-pathway-of-dna-double-strand-break-repair
#18
REVIEW
Vijay Menon, Lawrence F Povirk
Nonhomologous end joining (NHEJ) is an error-prone DNA double-strand break repair pathway that is active throughout the cell cycle. A substantial fraction of NHEJ repair events show deletions and, less often, insertions in the repair joints, suggesting an end-processing step comprising the removal of mismatched or damaged nucleotides by nucleases and other phosphodiesterases, as well as subsequent strand extension by polymerases. A wide range of nucleases, including Artemis, Metnase, APLF, Mre11, CtIP, APE1, APE2 and WRN, are biochemically competent to carry out such double-strand break end processing, and have been implicated in NHEJ by at least circumstantial evidence...
July 2016: DNA Repair
https://www.readbyqxmd.com/read/27220325/isoeugenol-is-a-selective-potentiator-of-camptothecin-cytotoxicity-in-vertebrate-cells-lacking-tdp1
#19
Waheba Elsayed, Lamia El-Shafie, Mohamed K Hassan, Mohamed A Farag, Sherif F El-Khamisy
Camptothecin (CPT), a topoisomerase I (TOP1) inhibitor, exhibits anti-tumor activity against a wide range of tumors. Redundancy of TOP1-mediated repair mechanisms is a major challenge facing the efficiency of TOP1-targetting therapies. This study aims to uncover new TOP1 targeting approaches utilising a selection of natural compounds in the presence or absence of tyrosyl DNA phosphodiesterase I (TDP1); a key TOP1-mediated protein-linked DNA break (PDB) repair enzyme. We identify, isoeugenol, a phenolic ether found in plant essential oils, as a potentiator of CPT cytotoxicity in Tdp1 deficient but not proficient cells...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27125028/-inhibitory-properties-of-nitrogen-containing-adamantane-derivatives-with-monoterpenoid-fragments-against-tyrosyl-dna-phosphodiesterase-i
#20
A L Zakharenko, K U Ponomarev, E V Suslov, D V Korchagina, K P Volcho, I A Vasil'eva, N F Salakhutdinov, O I Lavrik
It was found that compounds combining diazaadamantane and monoterpenoid fragments are potent inhibitors of new structural type of human recombinant DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1). It was demonstrated that the inhibition efficiency depended on the length and flexibility of the aliphatic chain of the substituent.
November 2015: Bioorganicheskaia Khimiia
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