Adenine-DNA adducts derived from the highly tumorigenic dibenzo[a,l]pyrene are resistant to nucleotide excision repair while guanine adducts are not

Konstantin Kropachev, Marina Kolbanovskiy, Zhi Liu, Yuqin Cai, Lu Zhang, Adam G. Schwaid, Alexander Kolbanovskiy, Shuang Ding, Shantu Amin, Suse Broyde, Nicholas E. Geacintov

Research output: Contribution to journalArticle

Abstract

The structural origins of differences in susceptibilities of various DNA lesions to nucleotide excision repair (NER) are poorly understood. Here we compared, in the same sequence context, the relative NER dual incision efficiencies elicited by two stereochemically distinct pairs of guanine (N 2-dG) and adenine (N6-dA) DNA lesions, derived from enantiomeric genotoxic diol epoxides of the highly tumorigenic fjord region polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P). Remarkably, in cell-free HeLa cell extracts, the guanine adduct with R absolute chemistry at the N2-dG linkage site is ∼35 times more susceptible to NER dual incisions than the stereochemically identical N6-dA adduct. For the guanine and adenine adducts with S stereochemistry, a similar but somewhat smaller effect (factor of ∼15) is observed. The striking resistance of the bulky N6-dA in contrast to the modest to good susceptibilities of the N2-dG adducts to NER is interpreted in terms of the balance between lesion-induced DNA distorting and DNA stabilizing van der Waals interactions in their structures, that are partly reflected in the overall thermal stabilities of the modified duplexes. Our results are consistent with the hypothesis that the high genotoxic activity of DB[a,l]P is related to the formation of NER-resistant and persistent DB[a,l]P-derived adenine adducts in cellular DNA.

Original languageEnglish (US)
Pages (from-to)783-793
Number of pages11
JournalChemical Research in Toxicology
Volume26
Issue number5
DOIs
StatePublished - May 20 2013

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DNA Adducts
Guanine
Adenine
DNA Repair
Repair
Nucleotides
DNA
Estuaries
Stereochemistry
Polycyclic Aromatic Hydrocarbons
Epoxy Compounds
Cell Extracts
HeLa Cells
Thermodynamic stability
Hot Temperature
dibenzo(a,l)pyrene

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

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Adenine-DNA adducts derived from the highly tumorigenic dibenzo[a,l]pyrene are resistant to nucleotide excision repair while guanine adducts are not. / Kropachev, Konstantin; Kolbanovskiy, Marina; Liu, Zhi; Cai, Yuqin; Zhang, Lu; Schwaid, Adam G.; Kolbanovskiy, Alexander; Ding, Shuang; Amin, Shantu; Broyde, Suse; Geacintov, Nicholas E.

In: Chemical Research in Toxicology, Vol. 26, No. 5, 20.05.2013, p. 783-793.

Research output: Contribution to journalArticle

Kropachev, Konstantin ; Kolbanovskiy, Marina ; Liu, Zhi ; Cai, Yuqin ; Zhang, Lu ; Schwaid, Adam G. ; Kolbanovskiy, Alexander ; Ding, Shuang ; Amin, Shantu ; Broyde, Suse ; Geacintov, Nicholas E. / Adenine-DNA adducts derived from the highly tumorigenic dibenzo[a,l]pyrene are resistant to nucleotide excision repair while guanine adducts are not. In: Chemical Research in Toxicology. 2013 ; Vol. 26, No. 5. pp. 783-793.
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T1 - Adenine-DNA adducts derived from the highly tumorigenic dibenzo[a,l]pyrene are resistant to nucleotide excision repair while guanine adducts are not

AU - Kropachev, Konstantin

AU - Kolbanovskiy, Marina

AU - Liu, Zhi

AU - Cai, Yuqin

AU - Zhang, Lu

AU - Schwaid, Adam G.

AU - Kolbanovskiy, Alexander

AU - Ding, Shuang

AU - Amin, Shantu

AU - Broyde, Suse

AU - Geacintov, Nicholas E.

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AB - The structural origins of differences in susceptibilities of various DNA lesions to nucleotide excision repair (NER) are poorly understood. Here we compared, in the same sequence context, the relative NER dual incision efficiencies elicited by two stereochemically distinct pairs of guanine (N 2-dG) and adenine (N6-dA) DNA lesions, derived from enantiomeric genotoxic diol epoxides of the highly tumorigenic fjord region polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P). Remarkably, in cell-free HeLa cell extracts, the guanine adduct with R absolute chemistry at the N2-dG linkage site is ∼35 times more susceptible to NER dual incisions than the stereochemically identical N6-dA adduct. For the guanine and adenine adducts with S stereochemistry, a similar but somewhat smaller effect (factor of ∼15) is observed. The striking resistance of the bulky N6-dA in contrast to the modest to good susceptibilities of the N2-dG adducts to NER is interpreted in terms of the balance between lesion-induced DNA distorting and DNA stabilizing van der Waals interactions in their structures, that are partly reflected in the overall thermal stabilities of the modified duplexes. Our results are consistent with the hypothesis that the high genotoxic activity of DB[a,l]P is related to the formation of NER-resistant and persistent DB[a,l]P-derived adenine adducts in cellular DNA.

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