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Molecular Modeling of the Major DNA Adduct Formed from Food Mutagen Ochratoxin A in NarI Two-Base Deletion Duplexes: Impact of Sequence Context and Adduct Ionization on Conformational Preference and Mutagenicity
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2017-08-08 00:00:00 , DOI: 10.1021/acs.chemrestox.7b00103
Preetleen Kathuria 1 , Purshotam Sharma 1 , Richard A. Manderville 2 , Stacey D. Wetmore 3
Affiliation  

Exposure to ochratoxin A (OTA), a possible human carcinogen, leads to many different DNA mutations. As a first step toward understanding the structural basis of OTA-induced mutagenicity, the present work uses a robust computational approach and a slipped mutagenic intermediate model previously studied for C8-dG aromatic amine adducts to analyze the conformational features of postreplication two-base deletion DNA duplexes containing OT-dG, the major OTA lesion at the C8 position of guanine. Specifically, a total of 960 ns of molecular dynamics simulations (excluding trial simulations) were carried out on four OT-dG ionization states in three sequence contexts within oligomers containing the NarI recognition sequence, a known hotspot for deletion mutations induced by related adducts formed from known carcinogens. Our results indicate that the structural properties and relative stability of the competing “major groove” and “stacked” conformations of OTA adducted two-base deletion duplexes depend on both the OTA ionization state and the sequence context, mainly due to conformation-dependent deviations in discrete local (hydrogen-bonding and stacking) interactions at the lesion site, as well as DNA bending. When the structural characteristics of the OT-dG adducted two-base deletion duplexes are compared to those associated with previously studied C8-dG adducts, a greater understanding of the effects of the nucleobase–carcinogen linkage, and size of the carcinogenic moiety on the conformational preferences of damaged DNA is obtained. Most importantly, our work predicts key structural features for OT-dG-adducted deletion DNA duplexes, which in turn allow us to develop hypotheses regarding OT-dG replication outcomes. Thus, our computational results are valuable for the design and interpretation of future biochemical studies on the potentially carcinogenic OT-dG lesion.

中文翻译:

食品诱变O曲霉毒素A在Nar I两碱基缺失双链体中形成的主要DNA加合物的分子模型:序列上下文和加合物电离对构象偏好和致突变性的影响。

暴露于to曲霉毒素A(OTA)(一种可能的人类致癌物)会导致许多不同的DNA突变。作为了解OTA诱导诱变的结构基础的第一步,本工作使用了可靠的计算方法和先前针对C 8 -dG芳香胺加合物研究的滑动诱变中间模型,以分析复制后两碱基缺失的构象特征。包含OT-dG的DNA双链体,OT-dG是鸟嘌呤C 8位的主要OTA病变。具体而言,在包含Nar的低聚物中的三个序列环境中,对四个OT-dG电离态进行了总共960 ns的分子动力学模拟(不包括试验模拟)。I识别序列,是由已知致癌物形成的相关加合物诱导的缺失突变的已知热点。我们的结果表明,OTA加成的两碱基缺失双链体竞争的“主要凹槽”和“堆积”构象的结构性质和相对稳定性均取决于OTA电离态和序列背景,这主要是由于构象依赖性的病变部位的离散局部(氢键和堆积)相互作用以及DNA弯曲。当将OT-dG加成的两碱基缺失双链体的结构特征与先前研究的C 8相关的结构特征进行比较时-dG加合物,可以更好地了解核碱基与致癌物之间的联系,以及致癌部分的大小对受损DNA构象偏好的影响。最重要的是,我们的工作预测了OT-dG加成的缺失DNA双链体的关键结构特征,这反过来又使我们能够得出有关OT-dG复制结果的假设。因此,我们的计算结果对于潜在致癌性OT-dG病变的未来生化研究的设计和解释是有价值的。
更新日期:2017-08-08
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