Biological Properties of Single Chemical−DNA Adducts: A Twenty Year Perspective

Delaney, James C.; Essigmann, John M.

doi:10.1021/tx700292a

Cited by 98 publications

(92 citation statements)

References 437 publications

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“…For example, each of the various G oxidation products has a different mutagenic potential in terms of both the type of mutation and the frequency (78). This is further complicated by the recognized role of sequence context as a determinant of polymerase fidelity not only in copying normal DNA but also in translesion synthesis (79).…”

Section: Discussionmentioning

confidence: 99%

DNA Sequence Context as a Determinant of the Quantity and Chemistry of Guanine Oxidation Produced by Hydroxyl Radicals and One-electron Oxidants

Margolin

Shafirovich

Geacintov

et al. 2008

Journal of Biological Chemistry

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DNA sequence context has emerged as a critical determinant of the location and quantity of nucleobase damage caused by many oxidizing agents. However, the complexity of nucleobase and 2-deoxyribose damage caused by strong oxidants such as ionizing radiation and the Fenton chemistry of Fe 2؉ -EDTA/ H 2 O 2 poses a challenge to defining the location of nucleobase damage and the effects of sequence context on damage chemistry in DNA. To address this problem, we developed a gel-based method that allows quantification of nucleobase damage in oxidized DNA by exploiting Escherichia coli exonuclease III to remove fragments containing direct strand breaks and abasic sites. The rigor of the method was verified in studies of guanine oxidation by photooxidized riboflavin and nitrosoperoxycarbonate, for which different effects of sequence context have been demonstrated by other approaches (Margolin, Y., Cloutier, J. F., Shafirovich, V., Geacintov, N. E., and Dedon, P. C. (2006) Nat. Chem. Biol. 2, 365-366). Using duplex oligodeoxynucleotides containing all possible three-nucleotide sequence contexts for guanine, the method was used to assess the role of DNA sequence context in hydroxyl radical-induced guanine oxidation associated with ␥-radiation and Fe 2؉ -EDTA/H 2 O 2 . The results revealed both differences and similarities for G oxidation by hydroxyl radicals and by one-electron oxidation by riboflavin-mediated photooxidation, which is consistent with the predominance of oxidation pathways for hydroxyl radicals other than one-electron oxidation to form guanine radical cations. Although the relative quantities of G oxidation produced by hydroxyl radicals were more weakly correlated with sequencespecific ionization potential than G oxidation produced by riboflavin, damage produced by both hydroxyl radical generators and riboflavin within two-and three-base runs of G showed biases in location that are consistent with a role for electron transfer in defining the location of the damage products. Furthermore, both ␥-radiation and Fe 2؉ -EDTA/H 2 O 2 showed relatively modest effects of sequence context on the proportions of different damage products sensitive to E. coli formamidopyrimidine DNA glycosylase and hot piperidine, although GT-containing sequence contexts displayed subtle biases in damage chemistry (formamidopyrimidine DNA glycosylase/piperidine ratio). Overall, the results are consistent with the known chemistry of guanine oxidation by hydroxyl radical and demonstrate that charge migration plays a relatively minor role in determining the location and chemistry of hydroxyl radical-mediated oxidative damage to guanine in DNA.With implications for mutagenesis and carcinogenesis, DNA damage caused by strong oxidizing agents such as ionizing radiation and Fenton chemistry (e.g. Fe 2ϩ -EDTA, Cu ϩ /H 2 O 2 ) affects both the base and sugar moieties (1, 2). This complexity poses a challenge to understanding the mechanisms of formation of the ultimate stable oxidation products and their relative amounts, especially in terms of...

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Section: Discussionmentioning

confidence: 99%

DNA Sequence Context as a Determinant of the Quantity and Chemistry of Guanine Oxidation Produced by Hydroxyl Radicals and One-electron Oxidants

Margolin

Shafirovich

Geacintov

et al. 2008

Journal of Biological Chemistry

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“…Intercalators are planar molecules that intercalate between the base pairs in the double-stranded DNA. Intercalation changes the shape of the double helix and can cause serine, and threonine residues), and N (primary aminogroups of lysine or arginine, secondary amino-group of histidine) (16 (17,18). The most common reaction between electrophiles and nucleophiles is alkylation, especially of purine at the N 7 site of guanine.…”

Section: Consequences Of Endogenous Dna Adduct Formationmentioning

confidence: 99%

Mutagenic and carcinogenic structural alerts and their mechanisms of action

Plošnik

Vračko

Dolenc

2016

Archives of Industrial Hygiene and Toxicology

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Knowing the mutagenic and carcinogenic properties of chemicals is very important for their hazard (and risk) assessment. One of the crucial events that trigger genotoxic and sometimes carcinogenic effects is the forming of adducts between chemical compounds and nucleic acids and histones. This review takes a look at the mechanisms related to specific functional groups (structural alerts or toxicophores) that may trigger genotoxic or epigenetic effects in the cells. We present up-to-date information about defined structural alerts with their mechanisms and the software based on this knowledge (QSAR models and classification schemes).

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“…Some of the most chemically-fascinating forms of DNA damage occur through reactions involving radicals, which may be generated naturally (i.e., as byproducts from cellular metabolism) [1][2][3][4] or from exposure to external sources (i.e., UV or ionizing radiation). [5][6][7][8] DNA damaged products, such as cyclobutane pyrimidine dimers 9 and nucleobase cross-links, [10][11][12][13] as well as DNA strand breaks 12 and other tandem lesions, 6,[12][13][14][15] arise from radical-initiated reactions between adjacent nucleotides within the same strand. This class of DNA damage is of particular interest to computational chemists due to the high reactivity of radicals and the associated difficulty studying these reactions experimentally.…”

Section: Introductionmentioning

confidence: 99%

Developing a computational model that accurately reproduces the structural features of a dinucleoside monophosphate unit within B-DNA

Churchill

Wetmore

2011

Phys. Chem. Chem. Phys.

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The ability of a dinucleoside monophosphate to mimic the conformation of B-DNA was tested using a combination of different phosphate models (anionic, neutral, counterion), environments (gas, water), and density functionals (B3LYP, MPWB1K, M06-2X) with the 6-31G(d,p) basis set. Three sequences (5'-GX(Py)-3', where X(Py) = T, U or (Br)U) were considered, which vary in the (natural or modified) 3' pyrimidine nucleobase (X(Py)). These bases were selected due to their presence in natural DNA, structural similarity to T and/or applications in radical-initiated anti-tumour therapies. The accuracy of each of the 54 model, method and sequence combinations was judged based on the ability to reproduce key structural features of natural B-DNA, including the stacked base-base orientation and important backbone torsion angles. B3LYP yields distorted or tilted relative base-base orientations, while many computational challenges were encountered for MPWB1K. Despite wide use in computational studies of DNA, the neutral (protonated) phosphate model could not consistently predict a stacked arrangement for all sequences. In contrast, stacked base-base arrangements were obtained for all sequences with M06-2X in conjunction with both the anionic and (sodium) counterion phosphate models. However, comparison of calculated and experimental backbone conformations reveals the charge-neutralized counterion phosphate model best mimics B-DNA. Structures optimized with implicit solvent (water) are comparable to gas-phase structures, which suggests similar results should be obtained in an environment of intermediate polarity. We recommend the use of either gas-phase or water M06-2X optimizations with the counterion phosphate model to study the structure and/or reactivity of natural or modified DNA with a dinucleoside monophosphate.

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Biological Properties of Single Chemical−DNA Adducts: A Twenty Year Perspective

Cited by 98 publications

References 437 publications

DNA Sequence Context as a Determinant of the Quantity and Chemistry of Guanine Oxidation Produced by Hydroxyl Radicals and One-electron Oxidants

DNA Sequence Context as a Determinant of the Quantity and Chemistry of Guanine Oxidation Produced by Hydroxyl Radicals and One-electron Oxidants

Mutagenic and carcinogenic structural alerts and their mechanisms of action

Developing a computational model that accurately reproduces the structural features of a dinucleoside monophosphate unit within B-DNA

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