The stereochemistry of benzo[<i>a</i>]pyrene‐2′‐deoxyguanosine adducts affects DNA methylation by SssI and HhaI DNA methyltransferases

Subach, Oksana M.; Maltseva, D. V.; Shastry, Anant; Kolbanovskiy, Alexander; Klimašauskas, Saulius; Geacintov, Nicholas E.; Громова, Е. С.

doi:10.1111/j.1742-4658.2007.05754.x

Cited by 17 publications

(20 citation statements)

References 62 publications

(107 reference statements)

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“…The impact of (+)- and (-)- trans -B[ a ]PDE- N 2 -dG adducts and (+)- cis -B[ a ]PDE- N 2 -dG adduct on methylation of 18-mer DNA duplexes by M.SssI was studied earlier [7, 8]. However, in the present work, we focused on the impact of two types of intercalative adducts that were not examined before.…”

Section: Resultsmentioning

confidence: 99%

“…It is well established that the fluorescence of B[ a ]PDE-DNA adducts exhibits broad pyrene-like vibronic emission bands with maxima at ∼ 380-385 and 400-405 nm [8, 21, 22, 38]. The fluorescence of B[ a ]PDE- N 2 -dG adducts in DNA is strongly quenched by a solvent polarity-dependent electron transfer mechanism [36, 39-42].…”

Section: Resultsmentioning

confidence: 99%

“…Such damage in the cellular DNA may disturb the functioning of MTases and change the genomic methylation pattern. This suggestion was supported by strong decreases in methylation efficiencies of the prokaryotic MTases M.EcoRII, M.HhaI and M.SssI in the case of 18-mer DNA duplexes containing (+)- and (-)- trans -B[ a ]PDE- N 2 -dG and (+)- cis -B[ a ]PDE- N 2 -dG adducts [6-8]. These studies have shown that (1) the B[ a ]PDE lesions affect primarily the methylation reaction by decreasing the efficiency of the catalytic step rather than the binding of the enzymes to the carcinogen-DNA adducts, and that (2) the methylation efficiency is strongly dependent on adduct conformation and its position within the DNA substrate.…”

Section: Introductionmentioning

confidence: 93%

“…The guanine lesions are known to be positioned within the minor groove in the case of the trans -B[ a ]PDE- N 2 -dG adducts [15, 16], or assume base-displaced intercalated conformations in the case of the stereoisomeric cis -B[ a ]PDE- N 2 -dG adducts [17, 18], while the B[ a ]PDE- N 6 -dA adducts are intercalated from the major groove without base displacement [9, 19, 20]. We made use of the fact that B[ a ]PDE residues of B[ a ]P-derived adducts in double- and single-stranded DNA can be used as fluorescent probes of their microenvironment for studying their interactions with different proteins [8, 21-24]. …”

Section: Introductionmentioning

confidence: 99%

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Probing murine methyltransfease Dnmt3a interactions with benzo[a]pyrene‐modified DNA by fluorescence methods

et al. 2012

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Summary The impact of bulky carcinogen-DNA adducts positioned at or near recognition sites (CpG) of eukaryotic DNA methyltransferases on their catalytic activities is poorly understood. In this work we have employed site-specifically modified 30-mer oligodeoxyribonucleotides containing stereoisomeric benzo[a]pyrene diol epoxide (B[a]PDE)-derived guanine (B[a]PDE-N2-dG) or adenine (B[a]PDE-N6-dA) adducts of different conformations as substrates of catalytic domain of murine Dnmt3a (Dnmt3a-CD). The fluorescence of these lesions was used to examine interactions between Dnmt3a-CD and DNA. In B[a]PDE-DNA•Dnmt3a-CD complexes the intensity of fluorescence of the covalently bound B[a]PDE residues is enhanced relative to the protein-free value when the B[a]PDE is positioned in the minor groove ((+)- and (−)-trans-B[a]PDE-N2-dG adducts in the CpG site) and when it is intercalated on the 5′-side of the CpG site ((+)-trans- B[a]PDE-N6-dA adduct). The fluorescence of B[a]PDE-modified DNA•Dnmt3a-CD complexes exhibits only small changes when the B[a]PDE is intercalated with base displacement in (+)- and (−)-cis- B[a]PDE-N2-dG adducts and without base displacement in the (−)-trans- B[a]PDE-N6-dA adduct. The initial rates of methylation were significantly reduced by the minor groove trans-B[a]PDE-N2-dG adducts regardless of their position in the substrate and by the intercalated cis-B[a]PDE-N2-dG adducts within the CpG site. The observed changes in fluorescence and methylation rates are consistent with the flipping of the target cytosine and a catalytic loop motion within the DNA•Dnmt3a-CD complexes. In the presence of the regulatory factor Dnmt3L, an enhancement of the methylation rates and fluorescence were observed which is consistent with a Dnmt3L-mediated displacement of the catalytic loop towards the CpG site.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Probing murine methyltransfease Dnmt3a interactions with benzo[a]pyrene‐modified DNA by fluorescence methods

et al. 2012

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“…In addition, disposition of Hoechst 33258 in the DNA minor groove was demonstrated for type I and II complexes with poly(dGdC)·poly(dG-dC) 28 . Recently we found that the presence of a bulky benzo[a]pyrene residue in the DNA minor groove caused a dramatic decrease in prokaryotic MTases SssI and HhaI methylating capacity because of distortion of DNA contacts with the enzyme catalytic loop 29,30 . Superimposition of the DNA methyltransferase HhaI (M.HhaI-DNA) complex structure onto the Dnmt3a-CD structure showed high similarity of M.HhaI and Dnmt3a-CD catalytic loop conformations 7 .…”

Section: Resultsmentioning

confidence: 99%

Dimeric bisbenzimidazoles inhibit the DNA methylation catalyzed by the murine Dnmt3a catalytic domain

Cherepanova

Ivanov

Maltseva

et al. 2010

Journal of Enzyme Inhibition and Medicinal Chemistry

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Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

Chappell

Pogribny

Guyton

et al. 2016

Mutation Research/Reviews in Mutation Research

142

105

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Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as “carcinogenic to humans” (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments.

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The stereochemistry of benzo[a]pyrene‐2′‐deoxyguanosine adducts affects DNA methylation by SssI and HhaI DNA methyltransferases

Abstract: The polycyclic aromatic hydrocarbons are a wellknown class of ubiquitous environmental pollutants which are generated by incomplete combustion of organic matter. These compounds require metabolic activation to highly reactive diol epoxides to elicit their detrimental genotoxic effects [1]

Cited by 17 publications

References 62 publications

Probing murine methyltransfease Dnmt3a interactions with benzo[a]pyrene‐modified DNA by fluorescence methods

Probing murine methyltransfease Dnmt3a interactions with benzo[a]pyrene‐modified DNA by fluorescence methods

Dimeric bisbenzimidazoles inhibit the DNA methylation catalyzed by the murine Dnmt3a catalytic domain

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

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