Adenine鈥揇NA Adducts Derived from the Highly Tumorigenic Dibenzo[a,l]pyrene Are Resistant to Nucleotide Excision Repair while Guanine Adducts Are Not

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• 作者：Konstantin Kropachev ; Marina Kolbanovskiy ; Zhi Liu ; Yuqin Cai ; Lu Zhang ; Adam G. Schwaid ; Alexander Kolbanovskiy ; Shuang Ding ; Shantu Amin ; Suse Broyde ; Nicholas E. Geacintov
• 刊名：Chemical Research in Toxicology
• 出版年：2013
• 出版时间：May 20, 2013
• 年：2013
• 卷：26
• 期：5
• 页码：783-793
• 全文大小：504K
• 年卷期：v.26,no.5(May 20, 2013)
• ISSN：1520-5010

文摘

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 (N²-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.