The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
Bruce Demple - One of the best experts on this subject based on the ideXlab platform.
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ATF4-Dependent Oxidative Induction of the DNA Repair Enzyme Ape1 Counteracts Arsenite Cytotoxicity and Suppresses Arsenite-Mediated Mutagenesis
Molecular and Cellular Biology, 2007Co-Authors: Hua Fung, Bruce DempleAbstract:Arsenite is a human carcinogen causing skin, bladder, and lung tumors, but the cellular mechanisms underlying these effects remain unclear. We investigated expression of the essential base excision DNA Repair Enzyme apurinic endonuclease 1 (Ape1) in response to sodium arsenite. In mouse 10T½ fibroblasts, Ape1 induction in response to arsenite occurred about equally at the mRNA, protein, and Enzyme activity levels. Analysis of the APE1 promoter region revealed an AP-1/CREB binding site essential for arsenite-induced transcriptional activation in both mouse and human cells. Electrophoretic mobility shift assays indicated that an ATF4/c-Jun heterodimer was the responsible transcription factor. RNA interference targeting c-Jun or ATF4 eliminated arsenite-induced APE1 transcription. Suppression of Ape1 or ATF4 sensitized both mouse fibroblasts (10T½) and human lymphoblastoid cells (TK6) to arsenite cytotoxicity. Expression of Ape1 from a transgene did not efficiently restore arsenite resistance in ATF4-depleted cells but did offset initial accumulation of abasic DNA damage following arsenite treatment. Mutagenesis by arsenite (at the TK and HPRT loci in TK6 cells) was observed only for ATF4-depleted cells, which was strongly offset by Ape1 expression from a transgene. Therefore, the ATF4-mediated up-regulation of Ape1 and other genes plays a key role against arsenite-mediated toxicity and mutagenesis.
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ATF4-Dependent Oxidative Induction of the DNA Repair Enzyme Ape1 Counteracts Arsenite Cytotoxicity and Suppresses Arsenite-Mediated Mutagenesis
Molecular and Cellular Biology, 2007Co-Authors: Hua Fung, Bruce DempleAbstract:Arsenite is a human carcinogen causing skin, bladder, and lung tumors, but the cellular mechanisms underlying these effects remain unclear. We investigated expression of the essential base excision DNA Repair Enzyme apurinic endonuclease 1 (Ape1) in response to sodium arsenite. In mouse 10T½ fibroblasts, Ape1 induction in response to arsenite occurred about equally at the mRNA, protein, and Enzyme activity levels. Analysis of the APE1 promoter region revealed an AP-1/CREB binding site essential for arsenite-induced transcriptional activation in both mouse and human cells. Electrophoretic mobility shift assays indicated that an ATF4/c-Jun heterodimer was the responsible transcription factor. RNA interference targeting c-Jun or ATF4 eliminated arsenite-induced APE1 transcription. Suppression of Ape1 or ATF4 sensitized both mouse fibroblasts (10T½) and human lymphoblastoid cells (TK6) to arsenite cytotoxicity. Expression of Ape1 from a transgene did not efficiently restore arsenite resistance in ATF4-depleted cells but did offset initial accumulation of abasic DNA damage following arsenite treatment. Mutagenesis by arsenite (at the TK and HPRT loci in TK6 cells) was observed only for ATF4-depleted cells, which was strongly offset by Ape1 expression from a transgene. Therefore, the ATF4-mediated up-regulation of Ape1 and other genes plays a key role against arsenite-mediated toxicity and mutagenesis.
Hua Fung - One of the best experts on this subject based on the ideXlab platform.
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ATF4-Dependent Oxidative Induction of the DNA Repair Enzyme Ape1 Counteracts Arsenite Cytotoxicity and Suppresses Arsenite-Mediated Mutagenesis
Molecular and Cellular Biology, 2007Co-Authors: Hua Fung, Bruce DempleAbstract:Arsenite is a human carcinogen causing skin, bladder, and lung tumors, but the cellular mechanisms underlying these effects remain unclear. We investigated expression of the essential base excision DNA Repair Enzyme apurinic endonuclease 1 (Ape1) in response to sodium arsenite. In mouse 10T½ fibroblasts, Ape1 induction in response to arsenite occurred about equally at the mRNA, protein, and Enzyme activity levels. Analysis of the APE1 promoter region revealed an AP-1/CREB binding site essential for arsenite-induced transcriptional activation in both mouse and human cells. Electrophoretic mobility shift assays indicated that an ATF4/c-Jun heterodimer was the responsible transcription factor. RNA interference targeting c-Jun or ATF4 eliminated arsenite-induced APE1 transcription. Suppression of Ape1 or ATF4 sensitized both mouse fibroblasts (10T½) and human lymphoblastoid cells (TK6) to arsenite cytotoxicity. Expression of Ape1 from a transgene did not efficiently restore arsenite resistance in ATF4-depleted cells but did offset initial accumulation of abasic DNA damage following arsenite treatment. Mutagenesis by arsenite (at the TK and HPRT loci in TK6 cells) was observed only for ATF4-depleted cells, which was strongly offset by Ape1 expression from a transgene. Therefore, the ATF4-mediated up-regulation of Ape1 and other genes plays a key role against arsenite-mediated toxicity and mutagenesis.
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ATF4-Dependent Oxidative Induction of the DNA Repair Enzyme Ape1 Counteracts Arsenite Cytotoxicity and Suppresses Arsenite-Mediated Mutagenesis
Molecular and Cellular Biology, 2007Co-Authors: Hua Fung, Bruce DempleAbstract:Arsenite is a human carcinogen causing skin, bladder, and lung tumors, but the cellular mechanisms underlying these effects remain unclear. We investigated expression of the essential base excision DNA Repair Enzyme apurinic endonuclease 1 (Ape1) in response to sodium arsenite. In mouse 10T½ fibroblasts, Ape1 induction in response to arsenite occurred about equally at the mRNA, protein, and Enzyme activity levels. Analysis of the APE1 promoter region revealed an AP-1/CREB binding site essential for arsenite-induced transcriptional activation in both mouse and human cells. Electrophoretic mobility shift assays indicated that an ATF4/c-Jun heterodimer was the responsible transcription factor. RNA interference targeting c-Jun or ATF4 eliminated arsenite-induced APE1 transcription. Suppression of Ape1 or ATF4 sensitized both mouse fibroblasts (10T½) and human lymphoblastoid cells (TK6) to arsenite cytotoxicity. Expression of Ape1 from a transgene did not efficiently restore arsenite resistance in ATF4-depleted cells but did offset initial accumulation of abasic DNA damage following arsenite treatment. Mutagenesis by arsenite (at the TK and HPRT loci in TK6 cells) was observed only for ATF4-depleted cells, which was strongly offset by Ape1 expression from a transgene. Therefore, the ATF4-mediated up-regulation of Ape1 and other genes plays a key role against arsenite-mediated toxicity and mutagenesis.
Alexandra L. Zakharenko - One of the best experts on this subject based on the ideXlab platform.
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The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme.
International journal of molecular sciences, 2020Co-Authors: Elizaveta D Gladkova, Alexandra L. Zakharenko, Arina A. Chepanova, I. V. Nechepurenko, Roman A. Bredikhin, Olga A. Luzina, Ekaterina S. Ilina, Nadezhda S. Dyrkheeva, Evgeniya Mamontova, Rashid O. AnarbaevAbstract:A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-Repair Enzyme. The berberine derivatives inhibit the Tdp1 Enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure-activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors.
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Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments.
Anti-cancer agents in medicinal chemistry, 2019Co-Authors: E. S. Mozhaitsev, Alexandra L. Zakharenko, E. V. Suslov, Dina V. Korchagina, Olga D. Zakharova, Inna A. Vasil'eva, Arina A. Chepanova, Ellena Black, Jinal Patel, Raina ChandAbstract:BACKGROUND AND OBJECTIVE The DNA Repair Enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 Enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDP1 inhibitors. METHODS New esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the Enzyme was modeling. RESULTS 13 Novel ester-based TDP1 inhibitors were synthesized with yields of 21-94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86-4.08 µM. Molecular modelling against the TDP1 crystal structure showed a good fit of the active esters in the catalytic pocket, explaining their potency. A non-toxic dose of ester, containing a 3,7- dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug, against the human lung adenocarcinoma cell line A549. CONCLUSION The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect.
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Synthesis and Inhibitory Properties of Imines Containing Monoterpenoid and Adamantane Fragments Against DNA Repair Enzyme Tyrosyl-DNA Phosphodiesterase 1 (Tdp1)
Chemistry of Natural Compounds, 2018Co-Authors: Alexandra L. Zakharenko, E. S. Mozhaitsev, E. V. Suslov, Dina V. Korchagina, Konstantin P. Volcho, Nariman F. Salakhutdinov, Olga I. LavrikAbstract:Six imines including four new ones were synthesized via the reaction of monoterpenoid aldehydes with aminoadamantanes. The inhibitory activities of the synthesized compounds against purified human recombinant DNA Repair Enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1) fell in the range IC50 = 5.5–7.1 μM.
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inhibitory properties of nitrogen containing adamantane derivatives with monoterpenoid fragments against tyrosyl DNA phosphodiesterase 1
Russian Journal of Bioorganic Chemistry, 2015Co-Authors: Alexandra L. Zakharenko, E. V. Suslov, Dina V. Korchagina, Konstantin P. Volcho, Nariman F. Salakhutdinov, K U Ponomarev, Inna A Vasileva, Olga I. LavrikAbstract:The compounds containing diazaadamantane and monoterpene moieties have been found to inhibit human purified recombinant tyrosyl-DNA phosphodiesterase 1 (Tdp1), a DNA Repair Enzyme. Several compounds have been shown to be potent inhibitors of a new structural type. Improved inhibition efficiency has been observed for compounds with longer aliphatic chains and increased flexibility of substituent.
N. K. Bernstein - One of the best experts on this subject based on the ideXlab platform.
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Mechanism of DNA substrate recognition by the mammalian DNA Repair Enzyme, Polynucleotide Kinase
Nucleic acids research, 2009Co-Authors: N. K. Bernstein, John A. Tainer, Michal Hammel, R. S. Mani, M. Weinfeld, M. Pelikan, J.n.m. GloverAbstract:Mammalian polynucleotide kinase (mPNK) is a critical DNA Repair Enzyme whose 5′-kinase and 3′-phoshatase activities function with poorly understood but striking specificity to restore 5′-phosphate/3′-hydroxyl termini at sites of DNA damage. Here we integrated site-directed mutagenesis and small-angle X-ray scattering (SAXS) combined with advanced computational approaches to characterize the conformational variability and DNA-binding properties of mPNK. The flexible attachment of the FHA domain to the catalytic segment, elucidated by SAXS, enables the interactions of mPNK with diverse DNA substrates and protein partners required for effective orchestration of DNA end Repair. Point mutations surrounding the kinase active site identified two substrate recognition surfaces positioned to contact distinct regions on either side of the phosphorylated 5′-hydroxyl. DNA substrates bind across the kinase active site cleft to position the double-stranded portion upstream of the 5′-hydroxyl on one side, and the 3′-overhang on the opposite side. The bipartite DNA-binding surface of the mPNK kinase domain explains its preference for recessed 5′-termini, structures that would be encountered in the course of DNA strand break Repair.
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the molecular architecture of the mammalian DNA Repair Enzyme polynucleotide kinase
Molecular Cell, 2005Co-Authors: N. K. Bernstein, R. S. Mani, Scott R Williams, Melissa L Rakovszky, Diana Cui, R Green, Feridoun Karimibusheri, Sarah Galicia, Anne C Koch, Carol E CassAbstract:Mammalian polynucleotide kinase (PNK) is a key component of both the base excision Repair (BER) and nonhomologous end-joining (NHEJ) DNA Repair pathways. PNK acts as a 5'-kinase/3'-phosphatase to create 5'-phosphate/3'-hydroxyl termini, which are a necessary prerequisite for ligation during Repair. PNK is recruited to Repair complexes through interactions between its N-terminal FHA domain and phosphorylated components of either pathway. Here, we describe the crystal structure of intact mammalian PNK and a structure of the PNK FHA bound to a cognate phosphopeptide. The kinase domain has a broad substrate binding pocket, which preferentially recognizes double-stranded substrates with recessed 5' termini. In contrast, the phosphatase domain efficiently dephosphorylates single-stranded 3'-phospho termini as well as double-stranded substrates. The FHA domain is linked to the kinase/phosphatase catalytic domain by a flexible tether, and it exhibits a mode of target selection based on electrostatic complementarity between the binding surface and the phosphothreonine peptide.
J.n.m. Glover - One of the best experts on this subject based on the ideXlab platform.
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Mechanism of DNA substrate recognition by the mammalian DNA Repair Enzyme, Polynucleotide Kinase
Nucleic acids research, 2009Co-Authors: N. K. Bernstein, John A. Tainer, Michal Hammel, R. S. Mani, M. Weinfeld, M. Pelikan, J.n.m. GloverAbstract:Mammalian polynucleotide kinase (mPNK) is a critical DNA Repair Enzyme whose 5′-kinase and 3′-phoshatase activities function with poorly understood but striking specificity to restore 5′-phosphate/3′-hydroxyl termini at sites of DNA damage. Here we integrated site-directed mutagenesis and small-angle X-ray scattering (SAXS) combined with advanced computational approaches to characterize the conformational variability and DNA-binding properties of mPNK. The flexible attachment of the FHA domain to the catalytic segment, elucidated by SAXS, enables the interactions of mPNK with diverse DNA substrates and protein partners required for effective orchestration of DNA end Repair. Point mutations surrounding the kinase active site identified two substrate recognition surfaces positioned to contact distinct regions on either side of the phosphorylated 5′-hydroxyl. DNA substrates bind across the kinase active site cleft to position the double-stranded portion upstream of the 5′-hydroxyl on one side, and the 3′-overhang on the opposite side. The bipartite DNA-binding surface of the mPNK kinase domain explains its preference for recessed 5′-termini, structures that would be encountered in the course of DNA strand break Repair.