Molecular modeling of the major benzo[a]pyrene N2-dG adduct in cases where mutagenesis results are known in double stranded DNA

Lee, Chiu Hong; Loechler, Edward L.

doi:10.1016/s0027-5107(03)00107-6

Cited by 7 publications

(11 citation statements)

References 99 publications

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“…Parameters for 8-oxo-G and Fapy·G are given in Supplementary Data. Preliminary minimizations followed previously established protocols ( 30 ), and, when needed, de novo DNA coordinates were generated from canonical fiber diffraction B-DNA ( 31 ). Structures with 8-oxo-G were compared with NMR and X-ray structures ( 32 , 33 ).…”

Section: Methodsmentioning

confidence: 99%

Genetic effects of oxidative DNA damages: comparative mutagenesis of the imidazole ring-opened formamidopyrimidines (Fapy lesions) and 8-oxo-purines in simian kidney cells

Kalam¹

2006

Nucleic Acids Research

131

147

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Fapy·dG and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) are formed in DNA by hydroxyl radical damage. In order to study replication past these lesions in cells, we constructed a single-stranded shuttle vector containing the lesion in 5′-TGT and 5′-TGA sequence contexts. Replication of the modified vector in simian kidney (COS-7) cells showed that Fapy·dG is mutagenic inducing primarily targeted Fapy·G→T transversions. In the 5′-TGT sequence mutational frequency of Fapy·dG was ∼30%, whereas in the 5′-TGA sequence it was ∼8%. In parallel studies 8-oxo-dG was found to be slightly less mutagenic than Fapy·dG, though it also exhibited a similar context effect: 4-fold G→T transversions (24% versus 6%) occurred in the 5′-TGT sequence relative to 5′-TGA. To investigate a possible structural basis for the higher G→T mutations induced by both lesions when their 3′ neighbor was T, we carried out a molecular modeling investigation in the active site of DNA polymerase β, which is known to incorporate both dCTP (no mutation) and dATP (G→T substitution) opposite 8-oxo-G. In pol β, the syn-8-oxo-G:dATP pair showed greater stacking with the 3′-T:A base pair in the 5′-TGT sequence compared with the 3′-A:T in the 5′-TGA sequence, whereas stacking for the anti-8-oxo-G:dCTP pair was similar in both 5′-TGT and 5′-TGA sequences. Similarly, syn-Fapy·G:dATP pairing showed greater stacking in the 5′-TGT sequence compared with the 5′-TGA sequence, while stacking for anti-Fapy·G:dCTP pairs was similar in the two sequences. Thus, for both lesions less efficient base stacking between the lesion:dATP pair and the 3′-A:T base pair in the 5′-TGA sequence might cause lower G→T mutational frequencies in the 5′-TGA sequence compared to 5′-TGT. The corresponding lesions derived from 2′-deoxyadenosine, Fapy·dA and 8-oxo-dA, were not detectably mutagenic in the 5′-TAT sequence, and were only weakly mutagenic (<1%) in the 5′-TAA sequence context, where both lesions induced targeted A→C transversions. To our knowledge this is the first investigation using extrachromosomal probes containing a Fapy·dG or Fapy·dA site-specifically incorporated, which showed unequivocally that in simian kidney cells Fapy·G→T substitutions occur at a higher frequency than 8-oxo-G→T and that Fapy·dA is very weakly mutagenic, as is 8-oxo-dA.

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Section: Methodsmentioning

confidence: 99%

Genetic effects of oxidative DNA damages: comparative mutagenesis of the imidazole ring-opened formamidopyrimidines (Fapy lesions) and 8-oxo-purines in simian kidney cells

Kalam¹

2006

Nucleic Acids Research

131

147

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“…Edward Loechler and Ashis Basu ,, performed pioneering work in the early days of site-specific mutagenesis while in this laboratory and have gone on to investigate other lesions and biological problems in their independent careers. Loechler has looked at the biological effects within E. coli of nitrogen mustard interstrand cross-links , and of sequence context and stereochemistry of benzo[ a ]pyrene- N 2 -guanine adducts – , combining observations from his single adduct studies with molecular modeling – . Basu has investigated N 2 -guanine adducts of nitropyrene and mitomycin C and C8-guanine adducts of nitropyrene and ammonia ,– in E. coli .…”

Section: In Vivo Lesion Replication and Repair Studiesmentioning

confidence: 99%

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

Delaney

Essigmann

2007

Chem. Res. Toxicol.

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The genome and its nucleotide precursor pool are under sustained attack by radiation, reactive oxygen and nitrogen species, chemical carcinogens, hydrolytic reactions, and certain drugs. As a result, a large and heterogeneous population of damaged nucleotides forms in all cells. Some of the lesions are repaired, but for those that remain, there can be serious biological consequences. For example, lesions that form in DNA can lead to altered gene expression, mutation, and death. This perspective examines systems developed over the past 20 years to study the biological properties of single DNA lesions.

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“…Most previous investigations of the effects of (+)-B a P DE-2 on DNA, both experimental ,, and theoretical, − have focused primarily on the covalent adducts with DNA oligomers or single nucleotides. Of particular recent interest has been the characterization of the conformational behavior of (+)-B a P DE-2-DNA adducts.…”

Section: Introductionmentioning

confidence: 99%

Noncovalent Interactions of a Benzo[a]pyrene Diol Epoxide with DNA Base Pairs: Insight into the Formation of Adducts of (+)-BaP DE-2 with DNA

et al. 2010

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Non-covalent complexes of a tumorigenic benzo[a]pyrene diol epoxide with the guanine-cytosine and adenine-thymine base pairs have been examined computationally. (+)-BaP DE-2 forms covalent adducts with DNA via nucleophilic attack on the (+)-BaP DE-2 epoxide. Computational results predict five thermodynamically accessible complexes of AT with (+)-BaP DE-2 that are compatible with intact DNA. Among these, two are expected to lead to adenine adducts. In the lowest energy AT...(+)-BaP DE-2 complex, which has a gas-phase interaction energy of −20.9 kcal mol−1, the exocyclic NH2 of adenine is positioned for backside epoxide attack and formation of a trans adduct. The most energetically favorable complex leading to formation of a cis ring-opened adduct lies only 0.6 kcal mol−1 higher in energy. For GC...(+)-BaP DE-2, there are only two thermodynamically accessible complexes. The higher-lying complex, bound in the gas phase by 24.4 kcal mol−1 relative to separated GC and (+)-BaP DE-2, would lead to a trans ring opened N2-guanine adduct. In the global minimum energy GC...(+)-BaP DE-2 complex, bound by 27.3 kcal mol−1, the exocyclic NH2 group of cytosine is positioned for cis epoxide addition. However, adducts of (+)-BaP DE-2 with cytosine are rarely observed experimentally. The paucity of cytosine adducts, despite the predicted thermodynamic stability of this GC...(+)-BaP DE-2 complex, is attributed to the electrostatic destabilization of the benzylic cation intermediate thought to precede cis addition.

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Molecular modeling of the major benzo[a]pyrene N2-dG adduct in cases where mutagenesis results are known in double stranded DNA

Cited by 7 publications

References 99 publications

Genetic effects of oxidative DNA damages: comparative mutagenesis of the imidazole ring-opened formamidopyrimidines (Fapy lesions) and 8-oxo-purines in simian kidney cells

Genetic effects of oxidative DNA damages: comparative mutagenesis of the imidazole ring-opened formamidopyrimidines (Fapy lesions) and 8-oxo-purines in simian kidney cells

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

Noncovalent Interactions of a Benzo[a]pyrene Diol Epoxide with DNA Base Pairs: Insight into the Formation of Adducts of (+)-BaP DE-2 with DNA

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