Kropachev Konstantin, Kolbanovskiy Marina, Liu Zhi, Cai Yuqin, Zhang Lu, Schwaid Adam G, Kolbanovskiy Alexander, Ding Shuang, Amin Shantu, Broyde Suse, Geacintov Nicholas E
Department of Chemistry, New York University , New York, New York 10003, United States.
Chem Res Toxicol. 2013 May 20;26(5):783-93. doi: 10.1021/tx400080k. Epub 2013 Apr 24.
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 (N(6)-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 N(2)-dG linkage site is ∼35 times more susceptible to NER dual incisions than the stereochemically identical N(6)-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 N(6)-dA in contrast to the modest to good susceptibilities of the N(2)-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.
各种DNA损伤对核苷酸切除修复（NER）敏感性差异的结构起源尚不清楚。在此，我们在相同的序列背景下，比较了由高致瘤性峡湾区域多环芳烃二苯并[a,l]芘（DB[a,l]P）的对映体基因毒性二醇环氧化物衍生的两对立体化学不同的鸟嘌呤（N(2)-dG）和腺嘌呤（N(6)-dA）DNA损伤引发的相对NER双切口效率。值得注意的是，在无细胞的HeLa细胞提取物中，在N(2)-dG连接位点具有R绝对化学构型的鸟嘌呤加合物比立体化学相同的N(6)-dA加合物对NER双切口的敏感性高约35倍。对于具有S立体化学构型的鸟嘌呤和腺嘌呤加合物，观察到类似但稍小的效应（约15倍）。与N(2)-dG加合物对NER的中等至良好敏感性相比，庞大的N(6)-dA具有显著抗性，这可以根据损伤诱导的DNA扭曲与它们结构中DNA稳定范德华相互作用之间的平衡来解释，这在一定程度上反映在修饰双链体的整体热稳定性上。我们的结果与以下假设一致，即DB[a,l]P的高基因毒性活性与细胞DNA中NER抗性和持久性DB[a,l]P衍生的腺嘌呤加合物的形成有关。
