The Experts below are selected from a list of 7011 Experts worldwide ranked by ideXlab platform
Dmitry O. Zharkov - One of the best experts on this subject based on the ideXlab platform.
-
Excision of 8-Oxoguanine from methylated CpG dinucleotides by human 8-Oxoguanine DNA glycosylase
FEBS letters, 2013Co-Authors: Rustem D. Kasymov, Inga Grin, Anton V. Endutkin, Serge L. Smirnov, Alexander A. Ishchenko, Murat Saparbaev, Dmitry O. ZharkovAbstract:CpG dinucleotides are targets for epigenetic methylation, many of them bearing 5-methylcytosine (mCyt) in the human genome. Guanine in this context can be easily oxidized to 8-Oxoguanine (oxoGua), which is repaired by 8-Oxoguanine-DNA glycosylase (OGG1). We have studied how methylation affects the efficiency of oxoGua excision from damaged CpG dinucleotides. Methylation of the adjacent cytosine moderately decreased the oxoGua excision rate while methylation opposite oxoGua lowered the rate of product release. Cytosine methylation abolished stimulation of OGG1 by repair endonuclease APEX1. The OGG1 S326C polymorphic variant associated with lung cancer showed poorer base excision and lost sensitivity to the opposite-base methylation. The overall repair in the system reconstituted from purified proteins decreased for CpG with mCyt in the damaged strand.
-
Thermodynamic and kinetic basis for recognition and repair of 8-Oxoguanine in DNA by human 8-Oxoguanine-DNA glycosylase
Nucleic acids research, 2011Co-Authors: Oleg O. Kirpota, Dmitry O. Zharkov, Anton V. Endutkin, Michail P. Ponomarenko, P. M. Ponomarenko, Georgy A. NevinskyAbstract:We have used a stepwise increase in ligand complexity approach to estimate the relative contributions of the nucleotide units of DNA containing 7,8-dihydro-8-Oxoguanine (oxoG) to its total affinity for human 8-Oxoguanine DNA glycosylase (OGG1) and construct thermodynamic models of the enzyme interaction with cognate and non-cognate DNA. Non-specific OGG1 interactions with 10–13nt pairs within its DNA-binding cleft provides approximately 5 orders of magnitude of its affinity for DNA
-
Specificity of stimulation of human 8-Oxoguanine-DNA glycosylase by AP endonuclease.
Biochemical and biophysical research communications, 2008Co-Authors: Viktoriya S. Sidorenko, Georgy A. Nevinsky, Dmitry O. ZharkovAbstract:Abstract Human 8-Oxoguanine–DNA glycosylase OGG1 is an enzyme that removes abundant oxidative lesion 8-Oxoguanine (8-oxoG) from DNA. Excision of 8-oxoG by OGG1 is inhibited by the abasic DNA reaction product and is stimulated by AP endonuclease APEX1. Besides 8-oxoG, OGG1 shows activity towards several other base lesions. Here we report that APEX1 efficiently stimulates OGG1 on good substrates (8-oxoadenine, 8-oxoinosine, or 6-methoxy-8-Oxoguanine opposite to cytosine) but the stimulation is low or absent with poor OGG1 substrates (8-oxoadenine or 8-oxoinosine opposite to thymine; 8-oxoG or 8-aminoguanine opposite to adenine; 8-oxonebularine, 8-metoxyguanine, inosine or guanine opposite to cytosine). APEX1 significantly improves the ability of OGG1 to excise 8-aminoguanine from its naturally occurring pair with cytosine, making it possible that OGG1 repairs this lesion. Overall, APEX1 serves to improve specificity of OGG1 for its biologically relevant substrates.
-
substrate discrimination by formamidopyrimidine dna glycosylase a mutational analysis
Journal of Biological Chemistry, 2004Co-Authors: Elena Zaika, R Gilboa, Rebecca A Perlow, Ethan Matz, Suse Broyde, Arthur P. Grollman, Dmitry O. ZharkovAbstract:Abstract Formamidopyrimidine-DNA glycosylase (Fpg) is a primary participant in the repair of 8-Oxoguanine, an abundant oxidative DNA lesion. Although the structure of Fpg has been established, amino acid residues that define damage recognition have not been identified. We have combined molecular dynamics and bioinformatics approaches to address this issue. Site-specific mutagenesis coupled with enzyme kinetics was used to test our predictions. On the basis of molecular dynamics simulations, Lys-217 was predicted to interact with the O8 of extrahelical 8-Oxoguanine accommodated in the binding pocket. Consistent with our computational studies, mutation of Lys-217 selectively reduced the ability of Fpg to excise 8-Oxoguanine from DNA. Dihydrouracil, also a substrate for Fpg, served as a nonspecific control. Other residues involved in damage recognition (His-89, Arg-108, and Arg-109) were identified by combined conservation/structure analysis. Arg-108, which forms two hydrogen bonds with cytosine in Fpg-DNA, is a major determinant of opposite-base specificity. Mutation of this residue reduced excision of 8-Oxoguanine from thermally unstable mispairs with guanine or thymine, while excision from the stable cytosine and adenine base pairs was less affected. Mutation of His-89 selectively diminished the rate of excision of 8-Oxoguanine, whereas mutation of Arg-109 nearly abolished binding of Fpg to damaged DNA. Taken together, these results suggest that His-89 and Arg-109 form part of a reading head, a structural feature used by the enzyme to scan DNA for damage. His-89 and Lys-217 help determine the specificity of Fpg in recognizing the oxidatively damaged base, while Arg-108 provides specificity for bases positioned opposite the lesion.
-
cloning and characterization of a mammalian 8 oxoguanine dna glycosylase
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Thomas A Rosenquist, Dmitry O. Zharkov, Arthur P. GrollmanAbstract:Oxidative DNA damage is generated by reactive oxygen species. The mutagenic base, 8-Oxoguanine, formed by this process, is removed from oxidatively damaged DNA by base excision repair. Genes coding for DNA repair enzymes that recognize 8-Oxoguanine have been reported in bacteria and yeast. We have identified and characterized mouse and human cDNAs encoding homologs of the 8-Oxoguanine DNA glycosylase (ogg1) gene of Saccharomyces cerevisiae. Escherichia coli doubly mutant for mutM and mutY have a mutator phenotype and are deficient in 8-Oxoguanine repair. The recombinant mouse gene (mOgg1) suppresses the mutator phenotype of mutY/mutM E. coli. Extracts prepared from mutY/mutM E. coli expressing mOgg1 contain an activity that excises 8-Oxoguanine from DNA and a β-lyase activity that nicks DNA 3′ to the lesion. The mouse ogg1 gene product acts efficiently on DNA duplexes in which 7,8-dihydroxy-8-oxo-2′-deoxyguanosine (8-oxodG) is paired with dC, acts weakly on duplexes in which 8-oxodG is paired with dT or dG, and is inactive against duplexes in which 8-oxodG is paired with dA. Mouse and human ogg1 genes contain a helix–hairpin–helix structural motif with conserved residues characteristic of a recently defined family of DNA glycosylases. Ogg1 mRNA is expressed in several mouse tissues; highest levels were detected in testes. Isolation of the mouse ogg1 gene makes it possible to modulate its expression in mice and to explore the involvement of oxidative DNA damage and associated repair processes in aging and cancer.
Sankar Mitra - One of the best experts on this subject based on the ideXlab platform.
-
activation of ras signaling pathway by 8 oxoguanine dna glycosylase bound to its excision product 8 oxoguanine
Journal of Biological Chemistry, 2012Co-Authors: Istvan Boldogh, Gyorgy Hajas, Leopoldo Aguileraaguirre, Muralidhar L Hegde, Zsolt Radak, Attila Bacsi, Tapas K Hazra, Sankar MitraAbstract:8-Oxo-7,8-dihydroguanine (8-oxoG), arguably the most abundant base lesion induced in mammalian genomes by reactive oxygen species, is repaired via the base excision repair pathway that is initiated with the excision of 8-oxoG by OGG1. Here we show that OGG1 binds the 8-oxoG base with high affinity and that the complex then interacts with canonical Ras family GTPases to catalyze replacement of GDP with GTP, thus serving as a guanine nuclear exchange factor. OGG1-mediated activation of Ras leads to phosphorylation of the mitogen-activated kinases MEK1,2/ERK1,2 and increasing downstream gene expression. These studies document for the first time that in addition to its role in repairing oxidized purines, OGG1 has an independent guanine nuclear exchange factor activity when bound to 8-oxoG.
-
acetylation of human 8 oxoguanine dna glycosylase by p300 and its role in 8 oxoguanine repair in vivo
Molecular and Cellular Biology, 2006Co-Authors: Kishor K Bhakat, Sanath K. Mokkapati, Istvan Boldogh, Tapas K Hazra, Sankar MitraAbstract:The human 8-Oxoguanine-DNA glycosylase 1 (OGG1) is the major DNA glycosylase responsible for repair of 7,8-dihydro-8-Oxoguanine (8-oxoG) and ring-opened fapyguanine, critical mutagenic DNA lesions that are induced by reactive oxygen species. Here we show that OGG1 is acetylated by p300 in vivo predominantly at Lys338/Lys341. About 20% of OGG1 is present in acetylated form in HeLa cells. Acetylation significantly increases OGG1's activity in vitro in the presence of AP-endonuclease by reducing its affinity for the abasic (AP) site product. The enhanced rate of repair of 8-oxoG in the genome by wild-type OGG1 but not the K338R/K341R mutant, ectopically expressed in oxidatively stressed OGG1-null mouse embryonic fibroblasts, suggests that acetylation increases OGG1 activity in vivo. At the same time, acetylation of OGG1 was increased by about 2.5-fold after oxidative stress with no change at the polypeptide level. OGG1 interacts with class I histone deacetylases, which may be responsible for its deacetylation. Based on these results, we propose a novel regulatory function of OGG1 acetylation in repair of its substrates in oxidatively stressed cells.
-
Stimulation of DNA Glycosylase Activity of OGG1 by NEIL1: Functional Collaboration between Two Human DNA Glycosylases†
Biochemistry, 2004Co-Authors: Sanath K. Mokkapati, Lee R Wiederhold, Tapan Kumar Hazra, Sankar MitraAbstract:The eukaryotic 8-Oxoguanine−DNA glycosylase 1 (OGG1) provides the major activity for repairing mutagenic 7,8-dihydro-8-Oxoguanine (8-oxoG) induced in the genome due to oxidative stress. Earlier in ...
James T Stivers - One of the best experts on this subject based on the ideXlab platform.
-
ap endonuclease 1 accelerates turnover of human 8 oxoguanine dna glycosylase by preventing retrograde binding to the abasic site product
Biochemistry, 2017Co-Authors: Alexandre Esadze, Gaddiel Rodriguez, Shannen L Cravens, James T StiversAbstract:A major product of oxidative DNA damage is 8-Oxoguanine. In humans, 8-Oxoguanine DNA glycosylase (hOGG1) facilitates removal of these lesions, producing an abasic (AP) site in the DNA that is subsequently incised by AP-endonuclease 1 (APE1). APE1 stimulates turnover of several glycosylases by accelerating rate-limiting product release. However, there have been conflicting accounts of whether hOGG1 follows a similar mechanism. In pre-steady-state kinetic measurements, we found that addition of APE1 had no effect on the rapid burst phase of 8-Oxoguanine excision by hOGG1 but accelerated steady-state turnover (kcat) by ∼10-fold. The stimulation by APE1 required divalent cations, could be detected under multiple-turnover conditions using limiting concentrations of APE1, did not require flanking DNA surrounding the hOGG1 lesion site, and occurred efficiently even when the first 49 residues of APE1’s N-terminus had been deleted. Stimulation by APE1 does not involve relief from product inhibition because thymine...
-
ap endonuclease 1 accelerates turnover of human 8 oxoguanine dna glycosylase by preventing retrograde binding to the abasic site product
Biochemistry, 2017Co-Authors: Alexandre Esadze, Gaddiel Rodriguez, Shannen L Cravens, James T StiversAbstract:A major product of oxidative DNA damage is 8-Oxoguanine. In humans, 8-Oxoguanine DNA glycosylase (hOGG1) facilitates removal of these lesions, producing an abasic (AP) site in the DNA that is subsequently incised by AP-endonuclease 1 (APE1). APE1 stimulates turnover of several glycosylases by accelerating rate-limiting product release. However, there have been conflicting accounts of whether hOGG1 follows a similar mechanism. In pre-steady-state kinetic measurements, we found that addition of APE1 had no effect on the rapid burst phase of 8-Oxoguanine excision by hOGG1 but accelerated steady-state turnover (kcat) by ∼10-fold. The stimulation by APE1 required divalent cations, could be detected under multiple-turnover conditions using limiting concentrations of APE1, did not require flanking DNA surrounding the hOGG1 lesion site, and occurred efficiently even when the first 49 residues of APE1’s N-terminus had been deleted. Stimulation by APE1 does not involve relief from product inhibition because thymine...
Sylvie Doublie - One of the best experts on this subject based on the ideXlab platform.
-
8 oxoguanine dna glycosylases one lesion three subfamilies
International Journal of Molecular Sciences, 2012Co-Authors: Frederick Faucher, Sylvie DoublieAbstract:Amongst the four bases that form DNA, guanine is the most susceptible to oxidation, and its oxidation product, 7,8-dihydro-8-Oxoguanine (8-oxoG) is the most prevalent base lesion found in DNA. Fortunately, throughout evolution cells have developed repair mechanisms, such as the 8-Oxoguanine DNA glycosylases (OGG), which recognize and excise 8-oxoG from DNA thereby preventing the accumulation of deleterious mutations. OGG are divided into three subfamilies, OGG1, OGG2 and AGOG, which are all involved in the base excision repair (BER) pathway. The published structures of OGG1 and AGOG, as well as the recent availability of OGG2 structures in both apo- and liganded forms, provide an excellent opportunity to compare the structural and functional properties of the three OGG subfamilies. Among the observed differences, the three-dimensional fold varies considerably between OGG1 and OGG2 members, as the latter lack the A-domain involved in 8-oxoG binding. In addition, all three OGG subfamilies bind 8-oxoG in a different manner even though the crucial interaction between the enzyme and the protonated N7 of 8-oxoG is conserved. Finally, the three OGG subfamilies differ with respect to DNA binding properties, helix-hairpin-helix motifs, and specificity for the opposite base.
-
8-Oxoguanine DNA glycosylases: one lesion, three subfamilies.
International journal of molecular sciences, 2012Co-Authors: Frederick Faucher, Sylvie Doublie, Zongchao JiaAbstract:Amongst the four bases that form DNA, guanine is the most susceptible to oxidation, and its oxidation product, 7,8-dihydro-8-Oxoguanine (8-oxoG) is the most prevalent base lesion found in DNA. Fortunately, throughout evolution cells have developed repair mechanisms, such as the 8-Oxoguanine DNA glycosylases (OGG), which recognize and excise 8-oxoG from DNA thereby preventing the accumulation of deleterious mutations. OGG are divided into three subfamilies, OGG1, OGG2 and AGOG, which are all involved in the base excision repair (BER) pathway. The published structures of OGG1 and AGOG, as well as the recent availability of OGG2 structures in both apo- and liganded forms, provide an excellent opportunity to compare the structural and functional properties of the three OGG subfamilies. Among the observed differences, the three-dimensional fold varies considerably between OGG1 and OGG2 members, as the latter lack the A-domain involved in 8-oxoG binding. In addition, all three OGG subfamilies bind 8-oxoG in a different manner even though the crucial interaction between the enzyme and the protonated N7 of 8-oxoG is conserved. Finally, the three OGG subfamilies differ with respect to DNA binding properties, helix-hairpin-helix motifs, and specificity for the opposite base.
-
crystal structures of two archaeal 8 oxoguanine dna glycosylases provide structural insight into guanine 8 oxoguanine distinction
Structure, 2009Co-Authors: Frederick Faucher, Susan S. Wallace, Viswanath Bandaru, Stephanie Duclos, Sylvie DoublieAbstract:Among the four DNA bases, guanine is particularly vulnerable to oxidative damage and the most common oxidative product, 7,8-dihydro-8-Oxoguanine (8-oxoG), is the most prevalent lesion observed in DNA molecules. Fortunately, 8-oxoG is recognized and excised by the 8-Oxoguanine DNA glycosylase (Ogg) of the base excision repair pathway. Ogg enzymes are divided into three separate families, namely, Ogg1, Ogg2, and archaeal GO glycosylase (AGOG). To date, structures of members of both Ogg1 and AGOG families are known but no structural information is available for members of Ogg2. Here we describe the first crystal structures of two archaeal Ogg2: Methanocaldococcus janischii Ogg and Sulfolobus solfataricus Ogg. A structural comparison with OGG1 and AGOG suggested that the C-terminal lysine of Ogg2 may play a key role in discriminating between guanine and 8-oxoG. This prediction was substantiated by measuring the glycosylase/lyase activity of a C-terminal deletion mutant of MjaOgg.
-
Crystal structures of two archaeal 8-Oxoguanine DNA glycosylases provide structural insight into guanine/8-Oxoguanine distinction.
Structure (London England : 1993), 2009Co-Authors: Frederick Faucher, Susan S. Wallace, Viswanath Bandaru, Stephanie Duclos, Sylvie DoublieAbstract:Among the four DNA bases, guanine is particularly vulnerable to oxidative damage and the most common oxidative product, 7,8-dihydro-8-Oxoguanine (8-oxoG), is the most prevalent lesion observed in DNA molecules. Fortunately, 8-oxoG is recognized and excised by the 8-Oxoguanine DNA glycosylase (Ogg) of the base excision repair pathway. Ogg enzymes are divided into three separate families, namely, Ogg1, Ogg2, and archaeal GO glycosylase (AGOG). To date, structures of members of both Ogg1 and AGOG families are known but no structural information is available for members of Ogg2. Here we describe the first crystal structures of two archaeal Ogg2: Methanocaldococcus janischii Ogg and Sulfolobus solfataricus Ogg. A structural comparison with OGG1 and AGOG suggested that the C-terminal lysine of Ogg2 may play a key role in discriminating between guanine and 8-oxoG. This prediction was substantiated by measuring the glycosylase/lyase activity of a C-terminal deletion mutant of MjaOgg.
Frederick Faucher - One of the best experts on this subject based on the ideXlab platform.
-
8 oxoguanine dna glycosylases one lesion three subfamilies
International Journal of Molecular Sciences, 2012Co-Authors: Frederick Faucher, Sylvie DoublieAbstract:Amongst the four bases that form DNA, guanine is the most susceptible to oxidation, and its oxidation product, 7,8-dihydro-8-Oxoguanine (8-oxoG) is the most prevalent base lesion found in DNA. Fortunately, throughout evolution cells have developed repair mechanisms, such as the 8-Oxoguanine DNA glycosylases (OGG), which recognize and excise 8-oxoG from DNA thereby preventing the accumulation of deleterious mutations. OGG are divided into three subfamilies, OGG1, OGG2 and AGOG, which are all involved in the base excision repair (BER) pathway. The published structures of OGG1 and AGOG, as well as the recent availability of OGG2 structures in both apo- and liganded forms, provide an excellent opportunity to compare the structural and functional properties of the three OGG subfamilies. Among the observed differences, the three-dimensional fold varies considerably between OGG1 and OGG2 members, as the latter lack the A-domain involved in 8-oxoG binding. In addition, all three OGG subfamilies bind 8-oxoG in a different manner even though the crucial interaction between the enzyme and the protonated N7 of 8-oxoG is conserved. Finally, the three OGG subfamilies differ with respect to DNA binding properties, helix-hairpin-helix motifs, and specificity for the opposite base.
-
8-Oxoguanine DNA glycosylases: one lesion, three subfamilies.
International journal of molecular sciences, 2012Co-Authors: Frederick Faucher, Sylvie Doublie, Zongchao JiaAbstract:Amongst the four bases that form DNA, guanine is the most susceptible to oxidation, and its oxidation product, 7,8-dihydro-8-Oxoguanine (8-oxoG) is the most prevalent base lesion found in DNA. Fortunately, throughout evolution cells have developed repair mechanisms, such as the 8-Oxoguanine DNA glycosylases (OGG), which recognize and excise 8-oxoG from DNA thereby preventing the accumulation of deleterious mutations. OGG are divided into three subfamilies, OGG1, OGG2 and AGOG, which are all involved in the base excision repair (BER) pathway. The published structures of OGG1 and AGOG, as well as the recent availability of OGG2 structures in both apo- and liganded forms, provide an excellent opportunity to compare the structural and functional properties of the three OGG subfamilies. Among the observed differences, the three-dimensional fold varies considerably between OGG1 and OGG2 members, as the latter lack the A-domain involved in 8-oxoG binding. In addition, all three OGG subfamilies bind 8-oxoG in a different manner even though the crucial interaction between the enzyme and the protonated N7 of 8-oxoG is conserved. Finally, the three OGG subfamilies differ with respect to DNA binding properties, helix-hairpin-helix motifs, and specificity for the opposite base.
-
crystal structures of two archaeal 8 oxoguanine dna glycosylases provide structural insight into guanine 8 oxoguanine distinction
Structure, 2009Co-Authors: Frederick Faucher, Susan S. Wallace, Viswanath Bandaru, Stephanie Duclos, Sylvie DoublieAbstract:Among the four DNA bases, guanine is particularly vulnerable to oxidative damage and the most common oxidative product, 7,8-dihydro-8-Oxoguanine (8-oxoG), is the most prevalent lesion observed in DNA molecules. Fortunately, 8-oxoG is recognized and excised by the 8-Oxoguanine DNA glycosylase (Ogg) of the base excision repair pathway. Ogg enzymes are divided into three separate families, namely, Ogg1, Ogg2, and archaeal GO glycosylase (AGOG). To date, structures of members of both Ogg1 and AGOG families are known but no structural information is available for members of Ogg2. Here we describe the first crystal structures of two archaeal Ogg2: Methanocaldococcus janischii Ogg and Sulfolobus solfataricus Ogg. A structural comparison with OGG1 and AGOG suggested that the C-terminal lysine of Ogg2 may play a key role in discriminating between guanine and 8-oxoG. This prediction was substantiated by measuring the glycosylase/lyase activity of a C-terminal deletion mutant of MjaOgg.
-
Crystal structures of two archaeal 8-Oxoguanine DNA glycosylases provide structural insight into guanine/8-Oxoguanine distinction.
Structure (London England : 1993), 2009Co-Authors: Frederick Faucher, Susan S. Wallace, Viswanath Bandaru, Stephanie Duclos, Sylvie DoublieAbstract:Among the four DNA bases, guanine is particularly vulnerable to oxidative damage and the most common oxidative product, 7,8-dihydro-8-Oxoguanine (8-oxoG), is the most prevalent lesion observed in DNA molecules. Fortunately, 8-oxoG is recognized and excised by the 8-Oxoguanine DNA glycosylase (Ogg) of the base excision repair pathway. Ogg enzymes are divided into three separate families, namely, Ogg1, Ogg2, and archaeal GO glycosylase (AGOG). To date, structures of members of both Ogg1 and AGOG families are known but no structural information is available for members of Ogg2. Here we describe the first crystal structures of two archaeal Ogg2: Methanocaldococcus janischii Ogg and Sulfolobus solfataricus Ogg. A structural comparison with OGG1 and AGOG suggested that the C-terminal lysine of Ogg2 may play a key role in discriminating between guanine and 8-oxoG. This prediction was substantiated by measuring the glycosylase/lyase activity of a C-terminal deletion mutant of MjaOgg.
