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https://www.readbyqxmd.com/read/28794467/tdp2-suppresses-chromosomal-translocations-induced-by-dna-topoisomerase-ii-during-gene-transcription
#1
Fernando Gómez-Herreros, Guido Zagnoli-Vieira, Ioanna Ntai, María Isabel Martínez-Macías, Rhona M Anderson, Andrés Herrero-Ruíz, Keith W Caldecott
DNA double-strand breaks (DSBs) induced by abortive topoisomerase II (TOP2) activity are a potential source of genome instability and chromosome translocation. TOP2-induced DNA double-strand breaks are rejoined in part by tyrosyl-DNA phosphodiesterase 2 (TDP2)-dependent non-homologous end-joining (NHEJ), but whether this process suppresses or promotes TOP2-induced translocations is unclear. Here, we show that TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity in breast cancer cells and at the translocation 'hotspot', MLL...
August 10, 2017: Nature Communications
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/28611105/the-dna-binding-polyamine-moiety-in-the-vectorized-dna-topoisomerase-ii-inhibitor-f14512-alters-reparability-of-the-consequent-enzyme-linked-dna-double-strand-breaks
#3
Oriane Bombarde, Florence Larminat, Dennis Gomez, Philippe Frit, Carine Racca, Bruno Gomes, Nicolas Guilbaud, Patrick Calsou
Poisons of Topoisomerase II (TOP2) kill cancer cells by preventing religation of intermediate DNA breaks during the enzymatic process and thus by accumulating enzyme-drug-DNA complexes called TOP2 cleavage-complex (TOP2cc). F14512 is a highly cytotoxic polyamine-vectorized TOP2 inhibitor derived from etoposide and currently in clinical trials. It was shown in vitro that F14512 has acquired DNA binding properties and that the stability of TOP2cc was strongly increased. Paradoxically, at equitoxic concentrations in cells, F14512 induced less DNA breaks than etoposide...
June 13, 2017: Molecular Cancer Therapeutics
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
#4
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/28393177/difficulty-in-obtaining-the-complete-mrna-coding-sequence-at-5-%C3%A2-region-5-%C3%A2-end-mrna-artifact-causes-consequences-in-biology-and-medicine-and-possible-solutions-for-obtaining-the-actual-amino-acid-sequence-of-proteins-review
#5
REVIEW
Lorenza Vitale, Maria Caracausi, Raffaella Casadei, Maria Chiara Pelleri, Allison Piovesan
The known difficulty in obtaining the actual full length, complete sequence of a messenger RNA (mRNA) may lead to the erroneous determination of its coding sequence at the 5' region (5' end mRNA artifact), and consequently to the wrong assignment of the translation start codon, leading to the inaccurate prediction of the encoded polypeptide at its amino terminus. Among the known human genes whose study was affected by this artifact, we can include disco interacting protein 2 homolog A (DIP2A; KIAA0184), Down syndrome critical region 1 (DSCR1), SON DNA binding protein (SON), trefoil factor 3 (TFF3) and URB1 ribosome biogenesis 1 homolog (URB1; KIAA0539) on chromosome 21, as well as receptor for activated C kinase 1 (RACK1, also known as GNB2L1), glutaminyl‑tRNA synthetase (QARS) and tyrosyl-DNA phosphodiesterase 2 (TDP2) along with another 474 loci, including interleukin 16 (IL16)...
May 2017: International Journal of Molecular Medicine
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/27943678/cytotoxicity-of-tirapazamine-3-amino-1-2-4-benzotriazine-1-4-dioxide-induced-dna-damage-in-chicken-dt40-cells
#7
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/27814490/mre11-is-essential-for-the-removal-of-lethal-topoisomerase-2-covalent-cleavage-complexes
#8
Nguyen Ngoc Hoa, Tsubasa Shimizu, Zhong Wei Zhou, Zhao-Qi Wang, Rajashree A Deshpande, Tanya T Paull, Salma Akter, Masataka Tsuda, Ryohei Furuta, Ken Tsusui, Shunichi Takeda, Hiroyuki Sasanuma
The Mre11/Rad50/Nbs1 complex initiates double-strand break repair by homologous recombination (HR). Loss of Mre11 or its nuclease activity in mouse cells is known to cause genome aberrations and cellular senescence, although the molecular basis for this phenotype is not clear. To identify the origin of these defects, we characterized Mre11-deficient (MRE11(-/-)) and nuclease-deficient Mre11 (MRE11(-/H129N)) chicken DT40 and human lymphoblast cell lines. These cells exhibit increased spontaneous chromosomal DSBs and extreme sensitivity to topoisomerase 2 poisons...
November 3, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27649880/roles-of-eukaryotic-topoisomerases-in-transcription-replication-and-genomic-stability
#9
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/27543075/novel-tdp2-ubiquitin-interactions-and-their-importance-for-the-repair-of-topoisomerase-ii-mediated-dna-damage
#10
Timsi Rao, Rui Gao, Saeko Takada, Muthana Al Abo, Xiang Chen, Kylie J Walters, Yves Pommier, Hideki Aihara
Tyrosyl DNA phosphodiesterase 2 (TDP2) is a multifunctional protein implicated in DNA repair, signal transduction and transcriptional regulation. In its DNA repair role, TDP2 safeguards genome integrity by hydrolyzing 5'-tyrosyl DNA adducts formed by abortive topoisomerase II (Top2) cleavage complexes to allow error-free repair of DNA double-strand breaks, thereby conferring cellular resistance against Top2 poisons. TDP2 consists of a C-terminal catalytic domain responsible for its phosphodiesterase activity, and a functionally uncharacterized N-terminal region...
December 1, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27262595/discovery-of-selective-inhibitors-of-tyrosyl-dna-phosphodiesterase-2-by-targeting-the-enzyme-dna-binding-cleft
#11
Bradley R Kossmann, Monica Abdelmalak, Sophia Lopez, Gabrielle Tender, Chunli Yan, Yves Pommier, Christophe Marchand, Ivaylo Ivanov
Tyrosyl-DNA phosphodiesterase 2 (TDP2) processes protein/DNA adducts resulting from abortive DNA topoisomerase II (Top2) activity. TDP2 inhibition could provide synergism with the Top2 poison class of chemotherapeutics. By virtual screening of the NCI diversity small molecule database, we identified selective TDP2 inhibitors and experimentally verified their selective inhibitory activity. Three inhibitors exhibited low-micromolar IC50 values. Molecular dynamics simulations revealed a common binding mode for these inhibitors, involving association to the TDP2 DNA-binding cleft...
July 15, 2016: Bioorganic & Medicinal Chemistry Letters
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
#12
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/27235629/depletion-of-tyrosyl-dna-phosphodiesterase-2-activity-enhances-etoposide-mediated-double-strand-break-formation-and-cell-killing
#13
Yasemin Saygideger Kont, Arijit Dutta, Apurva Mallisetty, Jeena Mathew, Tsion Minas, Christina Kraus, Priyanka Dhopeshwarkar, Bhaskar Kallakury, Sankar Mitra, Aykut Üren, Sanjay Adhikari
DNA topoisomerase 2 (Top2) poisons, including common anticancer drugs etoposide and doxorubicin kill cancer cells by stabilizing covalent Top2-tyrosyl-DNA 5'-phosphodiester adducts and DNA double-strand breaks (DSBs). Proteolytic degradation of the covalently attached Top2 leaves a 5'-tyrosylated blocked termini which is removed by tyrosyl DNA phosphodiesterase 2 (TDP2), prior to DSB repair through non-homologous end joining (NHEJ). Thus, TDP2 confers resistance of tumor cells to Top2-poisons by repairing such covalent DNA-protein adducts, and its pharmacological inhibition could enhance the efficacy of Top2-poisons...
July 2016: DNA Repair
https://www.readbyqxmd.com/read/27220325/isoeugenol-is-a-selective-potentiator-of-camptothecin-cytotoxicity-in-vertebrate-cells-lacking-tdp1
#14
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/27128689/deazaflavin-inhibitors-of-tyrosyl-dna-phosphodiesterase-2-tdp2-specific-for-the-human-enzyme-and-active-against-cellular-tdp2
#15
Christophe Marchand, Monica Abdelmalak, Jayakanth Kankanala, Shar-Yin Huang, Evgeny Kiselev, Katherine Fesen, Kayo Kurahashi, Hiroyuki Sasanuma, Shunichi Takeda, Hideki Aihara, Zhengqiang Wang, Yves Pommier
Tyrosyl-DNA phosphodiesterase 2 repairs irreversible topoisomerase II-mediated cleavage complexes generated by anticancer topoisomerase-targeted drugs and processes replication intermediates for picornaviruses (VPg unlinkase) and hepatitis B virus. There is currently no TDP2 inhibitor in clinical development. Here, we report a series of deazaflavin derivatives that selectively inhibit the human TDP2 enzyme in a competitive manner both with recombinant and native TDP2. We show that mouse, fish, and C. elegans TDP2 enzymes are highly resistant to the drugs and that key protein residues are responsible for drug resistance...
July 15, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27099339/mode-of-action-of-dna-competitive-small-molecule-inhibitors-of-tyrosyl-dna-phosphodiesterase-2
#16
Peter Hornyak, Trevor Askwith, Sarah Walker, Emilia Komulainen, Michael Paradowski, Lewis E Pennicott, Edward J Bartlett, Nigel C Brissett, Ali Raoof, Mandy Watson, Allan M Jordan, Donald J Ogilvie, Simon E Ward, John R Atack, Laurence H Pearl, Keith W Caldecott, Antony W Oliver
Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a 5'-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II (TOP2). TDP2 facilitates therapeutic resistance to topoisomerase poisons, which are widely used in the treatment of a range of cancer types. Consequently, TDP2 is an interesting target for the development of small molecule inhibitors that could restore sensitivity to topoisomerase-directed therapies. Previous studies identified a class of deazaflavin-based molecules that showed inhibitory activity against TDP2 at therapeutically useful concentrations, but their mode of action was uncertain...
July 1, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27060144/reversal-of-dna-damage-induced-topoisomerase-2-dna-protein-crosslinks-by-tdp2
#17
Matthew J Schellenberg, Lalith Perera, Christina N Strom, Crystal A Waters, Brinda Monian, C Denise Appel, Caroline K Vilas, Jason G Williams, Dale A Ramsden, R Scott Williams
Mammalian Tyrosyl-DNA phosphodiesterase 2 (Tdp2) reverses Topoisomerase 2 (Top2) DNA-protein crosslinks triggered by Top2 engagement of DNA damage or poisoning by anticancer drugs. Tdp2 deficiencies are linked to neurological disease and cellular sensitivity to Top2 poisons. Herein, we report X-ray crystal structures of ligand-free Tdp2 and Tdp2-DNA complexes with alkylated and abasic DNA that unveil a dynamic Tdp2 active site lid and deep substrate binding trench well-suited for engaging the diverse DNA damage triggers of abortive Top2 reactions...
May 5, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/26910725/isoquinoline-1-3-diones-as-selective-inhibitors-of-tyrosyl-dna-phosphodiesterase-ii-tdp2
#18
Jayakanth Kankanala, Christophe Marchand, Monica Abdelmalak, Hideki Aihara, Yves Pommier, Zhengqiang Wang
Tyrosyl DNA phosphodiesterase II (TDP2) is a recently discovered enzyme that specifically repairs DNA damages induced by topoisomerase II (Top2) poisons and causes resistance to these drugs. Inhibiting TDP2 is expected to enhance the efficacy of clinically important Top2-targeting anticancer drugs. However, TDP2 as a therapeutic target remains poorly understood. We report herein the discovery of isoquinoline-1,3-dione as a viable chemotype for selectively inhibiting TDP2. The initial hit compound 43 was identified by screening our in-house collection of synthetic compounds...
March 24, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26906474/synthesis-and-biological-evaluation-of-new-fluorinated-and-chlorinated-indenoisoquinoline-topoisomerase-i-poisons
#19
Daniel E Beck, Wei Lv, Monica Abdelmalak, Caroline B Plescia, Keli Agama, Christophe Marchand, Yves Pommier, Mark Cushman
Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds' activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogs were discovered through testing in human cancer cell cultures...
April 1, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/26701725/erk3-regulates-tdp2-mediated-dna-damage-response-and-chemoresistance-in-lung-cancer-cells
#20
Ka Bian, Naveen Reddy Muppani, Lobna Elkhadragy, Wei Wang, Cheng Zhang, Tenghui Chen, Sungyun Jung, Ole Morten Seternes, Weiwen Long
Posttranslational modifications (PTMs), such as phosphorylation and ubiquitination, play critical regulatory roles in the assembly of DNA damage response proteins on the DNA damage site and their activities in DNA damage repair. Tyrosyl DNA phosphodiesterase 2 (TDP2) repairs Topoisomerase 2 (Top2)-linked DNA damage, thereby protecting cancer cells against Top2 inhibitors-induced growth inhibition and cell death. The regulation of TDP2 activity by post-translational modifications in DNA repair, however, remains unclear...
February 9, 2016: Oncotarget
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