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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
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
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)...
September 21, 2016: Nature Reviews. Molecular Cell Biology
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
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...
July 25, 2016: Mechanisms of Ageing and Development
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
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
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
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
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
Zhuobin Liang, Sham Sunder, Sivakumar Nallasivam, Thomas E Wilson
Non-homologous end joining (NHEJ) is the main repair pathway for DNA double-strand breaks (DSBs) in cells with limited 5' resection. To better understand how overhang polarity of chromosomal DSBs affects NHEJ, we made site-specific 5'-overhanging DSBs (5' DSBs) in yeast using an optimized zinc finger nuclease at an efficiency that approached HO-induced 3' DSB formation. When controlled for the extent of DSB formation, repair monitoring suggested that chromosomal 5' DSBs were rejoined more efficiently than 3' DSBs, consistent with a robust recruitment of NHEJ proteins to 5' DSBs...
April 7, 2016: Nucleic Acids Research
N I Rechkunova, N A Lebedeva, O I Lavrik
Genomic DNA is constantly damaged by the action of exogenous factors and endogenous reactive metabolites. Apurinic/apyrimidinic sites (AP sites), which occur as a result of DNA glycosylase induced or spontaneous hydrolysis of the N-glycosidic bonds, are the most common damages of DNA. The chemical reactivity of AP sites is the cause of DNA breaks, and DNA-protein and DNA-DNA crosslinks. Repair of AP sites is one of the most important mechanisms for maintaining genome stability. Despite the fact that the main participants of the AP site repair are very well studied, the new proteins that could be involved potentially in this process as "back up" players or perform certain specialized functions are being found...
September 2015: Bioorganicheskaia Khimiia
Francisco Aresta-Branco, Silvia Pimenta, Luisa M Figueiredo
Antigenic variation in Trypanosoma brucei relies on periodic switching of variant surface glycoproteins (VSGs), which are transcribed monoallelically by RNA polymerase I from one of about 15 bloodstream expression sites (BES). Chromatin of the actively transcribed BES is depleted of nucleosomes, but it is unclear if this open conformation is a mere consequence of a high rate of transcription, or whether it is maintained by a transcription-independent mechanism. Using an inducible BES-silencing reporter strain, we observed that chromatin of the active BES remains open for at least 24 hours after blocking transcription...
April 20, 2016: Nucleic Acids Research
Kohei Tada, Masayuki Kobayashi, Yoko Takiuchi, Fumie Iwai, Takashi Sakamoto, Kayoko Nagata, Masanobu Shinohara, Katsuhiro Io, Kotaro Shirakawa, Masakatsu Hishizawa, Keisuke Shindo, Norimitsu Kadowaki, Kouji Hirota, Junpei Yamamoto, Shigenori Iwai, Hiroyuki Sasanuma, Shunichi Takeda, 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) and has a poor prognosis. We analyzed the cytotoxic effects of various nucleoside analog reverse transcriptase inhibitors (NRTIs) for HIV-1 on ATL cells and found that abacavir potently and selectively kills ATL cells. Although NRTIs have minimal genotoxicities on host cells, the therapeutic concentration of abacavir induced numerous DNA double-strand breaks (DSBs) in the chromosomal DNA of ATL cells...
April 2015: Science Advances
Agnese Cristini, Joon-Hyung Park, Giovanni Capranico, Gaëlle Legube, Gilles Favre, Olivier Sordet
Although defective repair of DNA double-strand breaks (DSBs) leads to neurodegenerative diseases, the processes underlying their production and signaling in non-replicating cells are largely unknown. Stabilized topoisomerase I cleavage complexes (Top1cc) by natural compounds or common DNA alterations are transcription-blocking lesions whose repair depends primarily on Top1 proteolysis and excision by tyrosyl-DNA phosphodiesterase-1 (TDP1). We previously reported that stabilized Top1cc produce transcription-dependent DSBs that activate ATM in neurons...
February 18, 2016: Nucleic Acids Research
Maxim Y Balakirev, James E Mullally, Adrien Favier, Nicole Assard, Eric Sulpice, David F Lindsey, Anastasia V Rulina, Xavier Gidrol, Keith D Wilkinson
Sumoylation during genotoxic stress regulates the composition of DNA repair complexes. The yeast metalloprotease Wss1 clears chromatin-bound sumoylated proteins. Wss1 and its mammalian analog, DVC1/Spartan, belong to minigluzincins family of proteases. Wss1 proteolytic activity is regulated by a cysteine switch mechanism activated by chemical stress and/or DNA binding. Wss1 is required for cell survival following UV irradiation, the smt3-331 mutation and Camptothecin-induced formation of covalent topoisomerase 1 complexes (Top1cc)...
2015: ELife
Natalia A Lebedeva, Rashid O Anarbaev, Maxim S Kupryushkin, Nadejda I Rechkunova, Dmitrii V Pyshnyi, Dmitry A Stetsenko, Olga I Lavrik
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) promotes catalytic scission of a phosphodiester bond between the 3'-end of DNA and the hydroxyl group of a tyrosine residue, as well as cleaving off a variety of other 3'-terminal phosphate-linked DNA substituents. We have shown recently that Tdp1 can initiate an apurinic/apyrimidinic (AP) site repair pathway that is independent from the one mediated by AP endonuclease 1 (APE1). Until recently, there was no method available of tracking the AP-site cleaving activity of Tdp1 by real-time fluorescence assay...
October 21, 2015: Bioconjugate Chemistry
Natalia A Lebedeva, Rashid O Anarbaev, Maria Sukhanova, Inna A Vasil'eva, Nadejda I Rechkunova, Olga I Lavrik
The influence of poly(ADP-ribose)polymerase 1 (PARP1) on the apurinic/apyrimidinic (AP)-site cleavage activity of tyrosyl-DNA phosphodiesterase 1 (TDP1) and interaction of PARP1 and TDP1 were studied. The efficiency of single or clustered AP-site hydrolysis catalysed by TDP1 was estimated. It was shown that the efficiency of AP-site cleavage increases in the presence of an additional AP-site in the opposite DNA strand depending on its position. PARP1 stimulates TDP1; the stimulation effect was abolished in the presence of NAD(+)...
2015: Bioscience Reports
Nathan J DeYonker, Charles Edwin Webster
Tyrosyl-DNA phosphodiesterase I (Tdp1) is a DNA repair enzyme conserved across eukaryotes that catalyzes the hydrolysis of the phosphodiester bond between the tyrosine residue of topoisomerase I and the 3'-phosphate of DNA. Atomic level details of the mechanism of Tdp1 are proposed and analyzed using a fully quantum mechanical, geometrically constrained model. The structural basis for the computational model is the vanadate-inhibited crystal structure of human Tdp1 (hTdp1, Protein Data Bank entry 1RFF ). Density functional theory computations are used to acquire thermodynamic and kinetic data along the catalytic pathway, including the phosphoryl transfer and subsequent hydrolysis...
July 14, 2015: Biochemistry
Rie Nakatani, Masayuki Nakamori, Harutoshi Fujimura, Hideki Mochizuki, Masanori P Takahashi
Trinucleotide repeat expansion disorders (TRED) are caused by genomic expansions of trinucleotide repeats, such as CTG and CAG. These expanded repeats are unstable in germline and somatic cells, with potential consequences for disease severity. Previous studies have demonstrated the involvement of DNA repair proteins in repeat instability, although the key factors affecting large repeat expansion and contraction are unclear. Here we investigated these factors in a human cell model harboring 800 CTG•CAG repeats by individually knocking down various DNA repair proteins using short interfering RNA...
2015: Scientific Reports
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