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https://www.readbyqxmd.com/read/29747023/assessment-of-dna-repair-susceptibility-genes-identified-by-whole-exome-sequencing-in-head-and-neck-cancer
#1
Raima Das, Sharbadeb Kundu, Shaheen Laskar, Yashmin Choudhury, Sankar Kumar Ghosh
Head and neck cancer (HNC), the sixth most common cancer globally, stands second in India. In Northeast (NE) India, it is the sixth most common cause of death in males and seventh in females. Prolonged tobacco and alcohol consumption constitute the major etiological factors for HNC development, which induce DNA damage. Therefore, DNA repair pathway is a crucial system in maintaining genomic integrity and preventing carcinogenesis. The present work was aimed to predict the consequence of significant germline variants of the DNA repair genes in disease predisposition...
April 26, 2018: DNA Repair
https://www.readbyqxmd.com/read/29677635/synthesis-and-structure-activity-relationship-of-furoquinolinediones-as-inhibitors-of-tyrosyl-dna-phosphodiesterase-2-tdp2
#2
Le-Mao Yu, Zhu Hu, Yu Chen, Azhar Ravji, Sophia Lopez, Caroline B Plescia, Qian Yu, Hui Yang, Monica Abdelmalak, Sourav Saha, Keli Agama, Evgeny Kiselev, Christophe Marchand, Yves Pommier, Lin-Kun An
Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a recently discovered enzyme specifically repairing topoisomerase II (TOP2)-mediated DNA damage. It has been shown that inhibition of TDP2 synergize with TOP2 inhibitors. Herein, we report the discovery of the furoquinolinedione chemotype as a suitable skeleton for the development of selective TDP2 inhibitors. Compound 1 was identified as a TDP2 inhibitor as a result of screening our in-house compound library for compounds selective for TDP2 vs. TDP1. Further SAR studies provide several selective TDP2 inhibitors at low-micromolar range...
April 12, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29574079/new-fluorescence-based-high-throughput-screening-assay-for-small-molecule-inhibitors-of-tyrosyl-dna-phosphodiesterase-2-tdp2
#3
Carlos J A Ribeiro, Jayakanth Kankanala, Ke Shi, Kayo Kurahashi, Evgeny Kiselev, Azhar Ravji, Yves Pommier, Hideki Aihara, Zhengqiang Wang
Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes resistance to TOP2-targeted cancer therapy. Inhibiting TDP2 could sensitize cancer cells toward TOP2 inhibitors. However, potent TDP2 inhibitors with favorable physicochemical properties are not yet reported. Therefore, there is a need to search for novel molecular scaffolds capable of inhibiting TDP2. We report herein a new simple, robust, homogenous mix-and-read fluorescence biochemical assay based using humanized zebrafish TDP2 (14M_zTDP2), which provides biochemical and molecular structure basis for TDP2 inhibitor discovery...
March 21, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29353210/vpg-unlinkase-tdp2-in-cardiovirus-infected-cells-re-localization-and-proteolytic-cleavage
#4
Sonia Maciejewski, Wendy Ullmer, Bert L Semler
Cardioviruses cause diseases in many animals including, in rare cases, humans. Although they share common features with all picornaviruses, cardioviruses have unique properties that distinguish them from other family members, including enteroviruses. One feature shared by all picornaviruses is the covalent attachment of VPg to the 5' end of genomic RNA via a phosphotyrosyl linkage. For enteroviruses, this linkage is cleaved by a host cell protein, TDP2. Since TDP2 is divergently required during enterovirus infections, we determined if TDP2 is necessary during infection by the prototype cardiovirus, EMCV...
March 2018: Virology
https://www.readbyqxmd.com/read/29216365/tyrosyl-dna-phosphodiesterases-rescuing-the-genome-from-the-risks-of-relaxation
#5
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...
January 25, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29172691/two-new-sesquiterpenes-derivatives-from-marine-fungus-leptosphaerulina-chartarum-sp-3608
#6
Panpan Zhang, Jing Li, Jiajia Lang, Chunxiu Jia, Shah-Iram Niaz, Senhua Chen, Lan Liu
Two new sesquiterpenes, leptoterpenes A (1) and B (2) were isolated from the fungus Leptosphaerulina Chartarum sp. 3608, derived from a crinoid. It was the first chemical study on this species. The structures of these compounds were elucidated by spectroscopic methods including NMR and MS spectrometry. The absolute configurations of the new compounds were determined on the basis of the single-crystal X-ray diffraction and electronic circular dichroism data analysis. All compounds were tested for their anti-inflammatory activity and the inhibitory effects on Tyrosyl DNA phosphodiesterase II (TDP2)...
November 26, 2017: Natural Product Research
https://www.readbyqxmd.com/read/29160298/tdp2-top2-and-sumo-what-is-zatt-about
#7
Guido Zagnoli-Vieira, Keith W Caldecott
Recently, ZATT (also known as ZNF451 or Zpf451) was reported by Schellenberg et al. to aid the removal of Topoisomerase II cleavage complexes by stimulating the phosphodiesterase activity of Tyrosyl DNA Phosphodiesterase 2. Although the full implication of this discovery is unknown, it will help us understand how cells respond to topoisomerase-induced genome damage and chemotherapeutic topoisomerase 'poisons'.
December 2017: Cell Research
https://www.readbyqxmd.com/read/29100048/novel-candidate-genes-of-the-park7-interactome-as-mediators-of-apoptosis-and-acetylation-in-multiple-sclerosis-an-in-silico-analysis
#8
George D Vavougios, Sotirios G Zarogiannis, Karen Angeliki Krogfelt, Konstantinos Gourgoulianis, Dimos Dimitrios Mitsikostas, Georgios Hadjigeorgiou
BACKGROUND: currently only 4 studies have explored the potential role of PARK7's dysregulation in MS pathophysiology Currently, no study has evaluated the potential role of the PARK7 interactome in MS. OBJECTIVE: The aim of our study was to assess the differential expression of PARK7 mRNA in peripheral blood mononuclears (PBMCs) donated from MS versus healthy patients using data mining techniques. METHODS: The PARK7 interactome data from the GDS3920 profile were scrutinized for differentially expressed genes (DEGs); Gene Enrichment Analysis (GEA) was used to detect significantly enriched biological functions...
January 2018: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/28912134/zatt-znf451-mediated-resolution-of-topoisomerase-2-dna-protein-cross-links
#9
Matthew J Schellenberg, Jenna Ariel Lieberman, Andrés Herrero-Ruiz, Logan R Butler, Jason G Williams, Ana M Muñoz-Cabello, Geoffrey A Mueller, Robert E London, Felipe Cortés-Ledesma, R Scott Williams
Topoisomerase 2 (TOP2) DNA transactions proceed via formation of the TOP2 cleavage complex (TOP2cc), a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. How genotoxic TOP2 DNA-protein cross-links are resolved is unclear. We found that the SUMO (small ubiquitin-related modifier) ligase ZATT (ZNF451) is a multifunctional DNA repair factor that controls cellular responses to TOP2 damage. ZATT binding to TOP2cc facilitates a proteasome-independent tyrosyl-DNA phosphodiesterase 2 (TDP2) hydrolase activity on stalled TOP2cc...
September 29, 2017: Science
https://www.readbyqxmd.com/read/28794467/tdp2-suppresses-chromosomal-translocations-induced-by-dna-topoisomerase-ii-during-gene-transcription
#10
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
#11
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/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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
Nguyen Ngoc Hoa, Tsubasa Shimizu, Zhong Wei Zhou, Zhao-Qi Wang, Rajashree A Deshpande, Tanya T Paull, Salma Akter, Masataka Tsuda, Ryohei Furuta, Ken Tsutsui, 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
#18
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
#19
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
#20
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
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