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https://www.readbyqxmd.com/read/29216365/tyrosyl-dna-phosphodiesterases-rescuing-the-genome-from-the-risks-of-relaxation
#1
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
https://www.readbyqxmd.com/read/29177742/studying-tdp1-function-in-dna-repair
#2
Shih-Chieh Chiang, Kirsty Liversidge, Sherif F El-Khamisy
Topoisomerase poisons act by inducing abortive topoisomerase reactions, which generate stable protein-DNA breaks (PDBs) that interfere with transcription elongation and progression of replication forks. In vertebrates, Tyrosyl-DNA phosphodiesterase 1 (TDP1) plays a major role in removal of topoisomerase 1-associated PDBs in the nucleus and mitochondria by hydrolyzing the 3'-phosphotyrosine bond. Depletion of TDP1 sensitizes tumor cells with defective DNA repair capacity to the genotoxic effect of TOP1 poisons, while homozygous mutation of the catalytic residue of TDP1 is associated with cerebellar degeneration and ataxia...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29167313/mechanism-informed-repurposing-of-minocycline-overcomes-resistance-to-topoisomerase-inhibition-for-peritoneal-carcinomatosis
#3
Huang-Chiao Huang, Joyce Liu, Yan Baglo, Imran Rizvi, Sriram Anbil, Michael Pigula, Tayyaba Hasan
Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and a rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL-8 respectively, thereby reinforcing the benefits of each modality...
November 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29100039/xrcc1-mediated-repair-of-strand-breaks-independent-of-pnkp-binding
#4
Julie K Horton, Donna F Stefanick, Ming-Lang Zhao, Agnes K Janoshazi, Natalie R Gassman, Hannah J Seddon, Samuel H Wilson
Repair of DNA-protein crosslinks and oxidatively damaged DNA base lesions generates intermediates with nicks or gaps with abnormal and blocked 3'-phosphate and 5'-OH ends that prevent the activity of DNA polymerases and ligases. End cleaning in mammalian cells by Tdp1 and PNKP produces the conventional 3'-OH and 5'-phosphate DNA ends suitable for completion of repair. This repair function of PNKP is facilitated by its binding to the scaffold protein XRCC1, and phosphorylation of XRCC1 by CK2 at several consensus sites enables PNKP binding and recruitment to DNA damage...
December 2017: DNA Repair
https://www.readbyqxmd.com/read/29099800/the-tyrosyl-dna-phosphodiesterase-1%C3%AE-tdp1%C3%AE-gene-discloses-an-early-response-to-abiotic-stresses
#5
Maria Elisa Sabatini, Andrea Pagano, Susana Araùjo, Alma Balestrazzi, Anca Macovei
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is involved in DNA repair pathways as it mends the topoisomerase I-DNA covalent complexes. In plants, a small Tdp1 gene family, composed by Tdp1α and Tdp1β genes, was identified, but the roles of these genes in abiotic stress responses are not fully understood. To investigate their specific stress response patterns, the present study made use of bioinformatic and molecular tools to look into the Tdp1β gene function, so far described only in the plant kingdom, and compare it with Tdp1α gene coding for the canonical, highly conserved α isoform...
November 3, 2017: Genes
https://www.readbyqxmd.com/read/29078113/tdp1-is-required-for-efficient-non-homologous-end-joining-in-human-cells
#6
Jing Li, Matthew Summerlin, Karin C Nitiss, John L Nitiss, Leslyn A Hanakahi
Tyrosyl-DNA phosphodiesterase 1 (TDP1) can remove a wide variety of 3' and 5' terminal DNA adducts. Genetic studies in yeast identified TDP1 as a regulator of non-homologous end joining (NHEJ) fidelity in the repair of double-strand breaks (DSBs) lacking terminal adducts. In this communication, we show that TDP1 plays an important role in joining cohesive DSBs in human cells. To investigate the role of TDP1 in NHEJ in live human cells we used CRISPR/cas9 to produce TDP1-knockout (TDP1-KO) HEK-293 cells. As expected, human TDP1-KO cells were highly sensitive to topoisomerase poisons and ionizing radiation...
December 2017: DNA Repair
https://www.readbyqxmd.com/read/29037996/synthesis-anti-cancer-screening-and-tyrosyl-dna-phosphodiesterase-1-tdp1-inhibition-activity-of-novel-piperidinyl-sulfamides
#7
Jung Ho Jun, Vineet Kumar, Thomas S Dexheimer, Iwona Wedlich, Marc C Nicklaus, Yves Pommier, Sanjay V Malhotra
Novel piperidinyl-based sulfamide derivatives were designed and synthesized through various synthetic routes. Anticancer activities of these sulfamides were evaluated by phenotypic screening on National Cancer Institute's 60 human tumor cell lines (NCI-60). Preliminary screening at 10μM concentration showed that piperidinyl sulfamide aminoester 26 (NSC 749204) was sensitive to most of the cell lines in the panel. Further dose-response studies showed that 26 was highly selective for inhibition of colon cancer cell lines with minimum GI50=1...
October 13, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28993637/htlv-1-bzip-factor-suppresses-tdp1-expression-through-inhibition-of-nrf-1-in-adult-t-cell-leukemia
#8
Yoko Takiuchi, Masayuki Kobayashi, Kohei Tada, Fumie Iwai, Maki Sakurada, Shigeki Hirabayashi, Kayoko Nagata, Kotaro Shirakawa, Keisuke Shindo, Jun-Ichirou Yasunaga, Yasuhiro Murakawa, Vinodh Rajapakse, Yves Pommier, Masao Matsuoka, Akifumi Takaori-Kondo
Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). We recently reported that abacavir, an anti-HIV-1 drug, potently and selectively kills ATL cells. This effect was attributed to the reduced expression of tyrosyl-DNA-phosphodiesterase 1 (TDP1), a DNA repair enzyme, in ATL cells. However, the molecular mechanism underlying the downregulation of TDP1 in ATL cells remains elusive. Here we identified the core promoter of the TDP1 gene, which contains a conserved nuclear respiratory factor 1 (NRF-1) binding site...
October 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28974547/common-tdp1-polymorphisms-in-relation-to-survival-among-small-cell-lung-cancer-patients-a-multicenter-study-from-the-international-lung-cancer-consortium
#9
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
https://www.readbyqxmd.com/read/28802254/tdp1-is-critical-for-the-repair-of-dna-breaks-induced-by-sapacitabine-a-nucleoside-also-targeting-atm-and-brca-deficient-tumors
#10
Muthana Al Abo, Hiroyuki Sasanuma, Xiaojun Liu, Vinodh N Rajapakse, Shar-Yin N Huang, Evgeny Kiselev, Shunichi Takeda, William Plunkett, Yves Pommier
2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes beta-elimination that generates single-strand breaks with abnormal 3'-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes non-phosphorylated 3'-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1-/- DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC...
August 11, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28740727/structure-modeling-of-human-tyrosyl-dna-phosphodiesterase-1-and-screening-for-its-inhibitors
#11
I V Gushchina, D K Nilov, A L Zakharenko, O I Lavrik, V K Švedas
The DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1) represents a potential molecular target for anticancer therapy. A human Tdp1 model has been constructed using the methods of quantum and molecular mechanics, taking into account the ionization states of the amino acid residues in the active site and their interactions with the substrate and competitive inhibitors. The oligonucleotide- and phosphotyrosine-binding cavities important for the inhibitor design have been identified in the enzyme's active site...
April 2017: Acta Naturae
https://www.readbyqxmd.com/read/28697309/identification-of-natural-products-that-inhibit-the-catalytic-function-of-human-tyrosyl-dna-phosphodiesterase-tdp1
#12
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
#13
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...
July 13, 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
#14
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...
August 2017: Genetics
https://www.readbyqxmd.com/read/28508041/mitochondrial-protein-linked-dna-breaks-perturb-mitochondrial-gene-transcription-and-trigger-free-radical-induced-dna-damage
#15
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
#16
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
#17
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
#18
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
#19
REVIEW
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...
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
#20
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
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