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Miral Dizdaroglu - One of the best experts on this subject based on the ideXlab platform.
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Evidence for the Involvement of DNA Repair Enzyme NEIL1 in Nucleotide Excision Repair of (5′R)- and (5′S)-8,5′-Cyclo-2′-deoxyadenosines
2015Co-Authors: Pawel Jaruga, Vladimir Vartanian, Yan Xiao, Stephen R. Lloyd, Miral DizdarogluAbstract:The DNA Repair Enzyme NEIL1 is a DNA glycosylase that is involved in the first step of base excision Repair (BER) of oxidatively induced DNA damage. NEIL1 exhibits a strong preference for excision of 4,6-diamino-5-formamidopyrimidine (FapyAde) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) from DNA with no specificity for 8-hydroxyguanine (8-OH-Gua). In this study, we report on the significant accumulation of (5′R)-8,5′-cyclo-2′-deoxyadenosine (R-cdA) and (5′S)-8,5′-cyclo-2′-deoxyadenosine (S-cdA) in liver DNA of neil1−/− mice that were not exposed to exogenous oxidative stress, while no accumulation of these lesions was observed in liver DNA from control or ogg1−/− mice. Significant accumulation of FapyGua was detected in liver DNA of both neil1−/− and ogg1−/− mice, while 8-OH-Gua accumulated in ogg1−/− only. Since R-cdA and S-cdA contain an 8,5′-covalent bond between the base and sugar moieties, they cannot be Repaired by BER. There is evidence that these lesions are Repaired by nucleotide excision Repair (NER). Since the accumulation of R-cdA and S-cdA in neil1−/− mice strongly points to the failure of their Repair, these data suggest that NEIL1 is involved in NER of R-cdA and S-cdA. Further studies aimed at elucidating the mechanism of action of NEIL1 in NER are warranted
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Evidence for the involvement of DNA Repair Enzyme NEIL1 in nucleotide excision Repair of (5'R)- and (5'S)-8,5'-cyclo-2'-deoxyadenosines.
Biochemistry, 2010Co-Authors: Pawel Jaruga, R. Stephen Lloyd, Vladimir Vartanian, Yan Xiao, Miral DizdarogluAbstract:The DNA Repair Enzyme NEIL1 is a DNA glycosylase that is involved in the first step of base excision Repair (BER) of oxidatively induced DNA damage. NEIL1 exhibits a strong preference for excision of 4,6-diamino-5-formamidopyrimidine (FapyAde) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) from DNA with no specificity for 8-hydroxyguanine (8-OH-Gua). In this study, we report on the significant accumulation of (5'R)-8,5'-cyclo-2'-deoxyadenosine (R-cdA) and (5'S)-8,5'-cyclo-2'-deoxyadenosine (S-cdA) in liver DNA of neil1(-/-) mice that were not exposed to exogenous oxidative stress, while no accumulation of these lesions was observed in liver DNA from control or ogg1(-/-) mice. Significant accumulation of FapyGua was detected in liver DNA of both neil1(-/-) and ogg1(-/-) mice, while 8-OH-Gua accumulated in ogg1(-/-) only. Since R-cdA and S-cdA contain an 8,5'-covalent bond between the base and sugar moieties, they cannot be Repaired by BER. There is evidence that these lesions are Repaired by nucleotide excision Repair (NER). Since the accumulation of R-cdA and S-cdA in neil1(-/-) mice strongly points to the failure of their Repair, these data suggest that NEIL1 is involved in NER of R-cdA and S-cdA. Further studies aimed at elucidating the mechanism of action of NEIL1 in NER are warranted.
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Evidence for the Involvement of DNA Repair Enzyme NEIL1 in Nucleotide Excision
2009Co-Authors: Pawel Jaruga, Vladimir Vartanian, Yan Xiao, Stephen R. Lloyd, Miral DizdarogluAbstract:ABSTRACT: The DNA Repair Enzyme NEIL1 is a DNA glycosylase that is involved in the first step of base excision Repair (BER) of oxidatively induced DNA damage. NEIL1 exhibits a strong preference for excision of 4,6-diamino-5-formamidopyrimidine (FapyAde) and 2,6-diamino-4hydroxy-5-formamidopyrimidine (FapyGua) from DNA with no specificity for 8-hydroxyguanine (8-OH-Gua). In this study, we report on the significant accumulation o
Stacey D. Wetmore - One of the best experts on this subject based on the ideXlab platform.
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Unveiling a Single-Metal-Mediated Phosphodiester Bond Cleavage Mechanism for Nucleic Acids: A Multiscale Computational Investigation of a Human DNA Repair Enzyme.
Journal of the American Chemical Society, 2019Co-Authors: Mohamed M. Aboelnga, Stacey D. WetmoreAbstract:Despite remarkable stability, the phosphodiester bond of nucleic acids is hydrolytically cleaved in critical biological processes. Although this reaction is commonly accepted to take place via a two-metal-assisted mechanism, recent experimental evidence suggests that several Enzymes use a single-metal ion, but the precise catalytic mechanism is unknown. In the present work, we employ a multiscale computational approach to decipher the phosphodiester cleavage mechanism for this unique pathway by focusing on the human APE1 Repair Enzyme, which catalyzes the incision of phosphodiester bonds adjacent to DNA lesions. To resolve ambiguity in the literature regarding the role of the single-metal (Mg(II)) center, several catalytic mechanisms were carefully examined. Our predicted preferred hydrolysis pathway proceeds in two steps via a pentacovalent phosphorane intermediate in the absence of substrate ligation to Mg(II), with a rate-limiting barrier (19.3 kcal/mol) in close agreement with experiment (18.3 kcal/mo...
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Unveiling a Single-Metal-Mediated Phosphodiester Bond Cleavage Mechanism for Nucleic Acids: A Multiscale Computational Investigation of a Human DNA Repair Enzyme
2019Co-Authors: Mohamed M. Aboelnga, Stacey D. WetmoreAbstract:Despite remarkable stability, the phosphodiester bond of nucleic acids is hydrolytically cleaved in critical biological processes. Although this reaction is commonly accepted to take place via a two-metal-assisted mechanism, recent experimental evidence suggests that several Enzymes use a single-metal ion, but the precise catalytic mechanism is unknown. In the present work, we employ a multiscale computational approach to decipher the phosphodiester cleavage mechanism for this unique pathway by focusing on the human APE1 Repair Enzyme, which catalyzes the incision of phosphodiester bonds adjacent to DNA lesions. To resolve ambiguity in the literature regarding the role of the single-metal (Mg(II)) center, several catalytic mechanisms were carefully examined. Our predicted preferred hydrolysis pathway proceeds in two steps via a pentacovalent phosphorane intermediate in the absence of substrate ligation to Mg(II), with a rate-limiting barrier (19.3 kcal/mol) in close agreement with experiment (18.3 kcal/mol). In this mechanism, D210 promotes catalysis by activating water for nucleophilic attack at the 5′-phosphate group with respect to the damaged site. Subsequently, a Mg(II)-bound water triggers leaving group departure by neutralizing the 3′-hydroxyl of the neighboring nucleotide. Consistent with experimental kinetic and mutational data, several other active site residues (N212, Y171, and H309) play multiple roles throughout the reaction to facilitate this challenging chemistry. In addition to revealing previously unknown mechanistic features of the APE1 catalyzed reaction, our work sets the stage for exploring the phosphodiester bond cleavage catalyzed by other single-metal-dependent Enzymes, as well as different pharmaceutical and biotechnological applications
Pawel Jaruga - One of the best experts on this subject based on the ideXlab platform.
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Evidence for the Involvement of DNA Repair Enzyme NEIL1 in Nucleotide Excision Repair of (5′R)- and (5′S)-8,5′-Cyclo-2′-deoxyadenosines
2015Co-Authors: Pawel Jaruga, Vladimir Vartanian, Yan Xiao, Stephen R. Lloyd, Miral DizdarogluAbstract:The DNA Repair Enzyme NEIL1 is a DNA glycosylase that is involved in the first step of base excision Repair (BER) of oxidatively induced DNA damage. NEIL1 exhibits a strong preference for excision of 4,6-diamino-5-formamidopyrimidine (FapyAde) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) from DNA with no specificity for 8-hydroxyguanine (8-OH-Gua). In this study, we report on the significant accumulation of (5′R)-8,5′-cyclo-2′-deoxyadenosine (R-cdA) and (5′S)-8,5′-cyclo-2′-deoxyadenosine (S-cdA) in liver DNA of neil1−/− mice that were not exposed to exogenous oxidative stress, while no accumulation of these lesions was observed in liver DNA from control or ogg1−/− mice. Significant accumulation of FapyGua was detected in liver DNA of both neil1−/− and ogg1−/− mice, while 8-OH-Gua accumulated in ogg1−/− only. Since R-cdA and S-cdA contain an 8,5′-covalent bond between the base and sugar moieties, they cannot be Repaired by BER. There is evidence that these lesions are Repaired by nucleotide excision Repair (NER). Since the accumulation of R-cdA and S-cdA in neil1−/− mice strongly points to the failure of their Repair, these data suggest that NEIL1 is involved in NER of R-cdA and S-cdA. Further studies aimed at elucidating the mechanism of action of NEIL1 in NER are warranted
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Evidence for the involvement of DNA Repair Enzyme NEIL1 in nucleotide excision Repair of (5'R)- and (5'S)-8,5'-cyclo-2'-deoxyadenosines.
Biochemistry, 2010Co-Authors: Pawel Jaruga, R. Stephen Lloyd, Vladimir Vartanian, Yan Xiao, Miral DizdarogluAbstract:The DNA Repair Enzyme NEIL1 is a DNA glycosylase that is involved in the first step of base excision Repair (BER) of oxidatively induced DNA damage. NEIL1 exhibits a strong preference for excision of 4,6-diamino-5-formamidopyrimidine (FapyAde) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) from DNA with no specificity for 8-hydroxyguanine (8-OH-Gua). In this study, we report on the significant accumulation of (5'R)-8,5'-cyclo-2'-deoxyadenosine (R-cdA) and (5'S)-8,5'-cyclo-2'-deoxyadenosine (S-cdA) in liver DNA of neil1(-/-) mice that were not exposed to exogenous oxidative stress, while no accumulation of these lesions was observed in liver DNA from control or ogg1(-/-) mice. Significant accumulation of FapyGua was detected in liver DNA of both neil1(-/-) and ogg1(-/-) mice, while 8-OH-Gua accumulated in ogg1(-/-) only. Since R-cdA and S-cdA contain an 8,5'-covalent bond between the base and sugar moieties, they cannot be Repaired by BER. There is evidence that these lesions are Repaired by nucleotide excision Repair (NER). Since the accumulation of R-cdA and S-cdA in neil1(-/-) mice strongly points to the failure of their Repair, these data suggest that NEIL1 is involved in NER of R-cdA and S-cdA. Further studies aimed at elucidating the mechanism of action of NEIL1 in NER are warranted.
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Evidence for the Involvement of DNA Repair Enzyme NEIL1 in Nucleotide Excision
2009Co-Authors: Pawel Jaruga, Vladimir Vartanian, Yan Xiao, Stephen R. Lloyd, Miral DizdarogluAbstract:ABSTRACT: The DNA Repair Enzyme NEIL1 is a DNA glycosylase that is involved in the first step of base excision Repair (BER) of oxidatively induced DNA damage. NEIL1 exhibits a strong preference for excision of 4,6-diamino-5-formamidopyrimidine (FapyAde) and 2,6-diamino-4hydroxy-5-formamidopyrimidine (FapyGua) from DNA with no specificity for 8-hydroxyguanine (8-OH-Gua). In this study, we report on the significant accumulation o
Martin Zacharias - One of the best experts on this subject based on the ideXlab platform.
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both dna global deformation and Repair Enzyme contacts mediate flipping of thymine dimer damage
Scientific Reports, 2017Co-Authors: Alexander Knips, Martin ZachariasAbstract:The photo-induced cis-syn-cyclobutane pyrimidine (CPD) dimer is a frequent DNA lesion. In bacteria photolyases efficiently Repair dimers employing a light-driven reaction after flipping out the CPD damage to the active site. How the Repair Enzyme identifies a damaged site and how the damage is flipped out without external energy is still unclear. Employing molecular dynamics free energy calculations, the CPD flipping process was systematically compared to flipping undamaged nucleotides in various DNA global states and bound to photolyase Enzyme. The global DNA deformation alone (without protein) significantly reduces the flipping penalty and induces a partially looped out state of the damage but not undamaged nucleotides. Bound Enzyme further lowers the penalty for CPD damage flipping with a lower free energy of the flipped nucleotides in the active site compared to intra-helical state (not for undamaged DNA). Both the reduced penalty and partial looping by global DNA deformation contribute to a significantly shorter mean first passage time for CPD flipping compared to regular nucleotides which increases the Repair likelihood upon short time encounter between Repair Enzyme and DNA.
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influence of a cis syn cyclobutane pyrimidine dimer damage on dna conformation studied by molecular dynamics simulations
Biopolymers, 2015Co-Authors: Alexander Knips, Martin ZachariasAbstract:The photo-induced formation of cis-syn-cyclobutane pyrimidine dimers (CPD) is a highly mutagenic and cancerogenic DNA lesion. In bacteria photolyases can efficiently reverse the dimer formation employing a light-driven reaction after looping out the CPD damaged bases into the Enzyme active site. The exact mechanism how the Repair Enzyme identifies a damaged site within a large surplus of undamaged DNA is not fully understood. The CPD damage may alter the DNA structure and dynamics already in the absence of the Repair Enzyme which can facilitate the initial binding of a photolyase Repair Enzyme. To characterize the effect of a CPD damage, extensive comparative molecular dynamics (MD) simulations on duplex DNA with central regular or CPD damaged nucleotides were performed supplemented with simulations of the DNA-photolyase complex. Although no spontaneous flipping out transitions of the damaged bases were observed, the simulations showed significant differences in the conformational states of regular and CPD damage DNA. The isolated damaged DNA adopted transient conformations which resembled the global shape of the Repair Enzyme bound conformation more closely compared to regular B-DNA. In particular, these conformational changes were observed in most of helical and structural parameters where the protein bound DNA differs drastically from regular B-DNA. It is likely that the transient overlap of isolated DNA with the Enzyme bound DNA conformation plays a decisive role for the specific and rapid initial recognition by the Repair Enzyme prior to the looping out process of the damaged DNA. © 2014 Wiley Periodicals, Inc. Biopolymers 103: 215–222, 2015.
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Influence of DNA Conformation and Repair Enzyme on Guanine and 8-Oxoguanine Base Flipping
Biophysical Journal, 2015Co-Authors: Giuseppe La Rosa, Martin ZachariasAbstract:8-oxoguanine (8oxoG) is an abundant product of oxidative damage in DNA and if not Repaired can result in mutations upon DNA replication. It is removed by Repair glycosylases (e.g. MutM-glycosylase in bacteria) after flipping out the damaged base towards an extra-helical conformation into the Repair Enzyme active site. The exact mechanism how the Repair Enzyme identifies a damaged site within a large surplus of undamaged DNA is not fully understood. Binding of a Repair Enzyme results also in significant DNA deformation such as bending and minor groove opening. Looping out nucleotides from an intra-helical base paired conformation is energetically costly and it is not clear how the presence of a Repair Enzyme or the deformation of DNA may facilitate the looping out process. In this study we use Molecular Dynamics free energy simulations to evaluate the effects of DNA deformation and Enzyme binding on the DNA base flipping process. The simulations indicate distinct free energy profiles for flipping 8oxoG or guanine and resulted in an overall calculated free energy for the flipping process in accordance with experimental imino proton exchange from Nuclear Magnetic Resonance spectroscopy. Distortion of the DNA towards a conformation as observed in complex with the Repair Enzyme lowered the free energy barrier and penalty for the flipping process. The result indicates that the DNA deformation induced by the Repair Enzyme binding has a significant influence on the flipping process. The additional effect of protein-DNA contacts on the calculated free energy for the flipping process will also be presented.
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.