Synthesis and Studies of Site-Specific Carcinogen-DNA Lesions

位点特异性致癌物-DNA损伤的合成与研究

• 批准号: 7574567
• 负责人: MAHESH K LAKSHMAN
• 金额: $ 17.74万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7574567
• 关键词: 2' -deoxyadenosine; Address; Adenine; Affect; Alkylating Agents; Alkylation; Appearance; Aromatic Hydrocarbons; Aromatic Polycyclic Hydrocarbons; Bay Region; Benzo(a)pyrene; Biochemical; Biological; Biology; Carcinogens; Chemistry; Codon Nucleotides; Collaborations; Comparative Study; Complex; Cytosine; DNA; DNA Adducts; DNA Alkylation; DNA Binding; DNA Damage; DNA Sequence; DNA Structure; DNA lesion; Data; Databases; Deoxyadenosines; Deoxyguanosine; Development; Environment; Epoxy Compounds; Ethylene Oxide; Evaluation; Event; Funding; Gamma-glutamyl transferase; Glean; Glycol; Goals; Guanine; Housing; Human; Individual; Influentials; Investigation; Isomerism; Lesion; Malignant Neoplasms; Measurement; Mediating; Metabolic Activation; Metabolism; Metals; Methodology; Methods; Minor; Modification; Molecular; Molecular Conformation; Mutation; Nucleosides; Object Attachment; Oregon; Outcome; Output; Palladium; Pliability; Polycyclic Hydrocarbons; Positioning Attribute; Process; Property; Proteins; Purines; Reaction; Research; Route; Scheme; Series; Site; Societies; Structure; System; Technology; Temperature; Testing; Time; Tumorigenicity; adduct; base; benzo(c)phenanthrene; carcinogenesis; chemical carcinogenesis; deoxyadenosine; enantiomer; falls; novel; prototype; purine; repaired; research study; response; single molecule; tumorigenesis; tumorigenic

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment and they pose a cancer threat to humans as they are products of activities in a modern society. Alternant bay and fjord region PAHs are metabolized to 4 isomeric diol epoxides that are potent DNA alkylating agents. Reaction of these diol epoxides with cellular DNA results in the formation of 16 nucleoside adducts; 8 isomers from deoxyadenosine (dA) and correspondingly 8 from deoxyguanosine (dG). The isomeric diol epoxides have markedly different tumorigenicities that implies differences in intracellular recognition, replication and repair the individual diol epoxide-nucleoside adducts. Thus, an understanding of the structural differences in the individual diol epoxide-DNA lesions in relation to the biological responses is expected to provide a better basis for understanding chemical carcinogenesis at the molecular level. The proposed studies are on two topologically different structural paradigms; the bay region represented by benzo[a]pyrene (BaP) and the fjord region represented by benzo[c]phenanthrene (BcPh) the DNA adducts of which are expected to elicit markedly different structural properties. One aim of the project is to complete delineation of novel, unequivocal synthesis of all diol epoxide-nucleoside adducts of these two PAHs. The methods that so evolve will potentially have general applicability for studies with any bay or fjord region PAH diol epoxide. The adducts will be incorporated into suitable DNA sequences (primarily human N-ras for the dA adducts and c-Ki-ras for the dG) for comparative studies within the individual sequence contexts. These include: 7m studies with normal and mismatched complementary strands, and temperature-dependent CD studies of the duplexes. The proposed synthesis encompasses ample flexibility to allow for the modification of any sequence or the incorporation of MeC adjacent to the dG adducts. Thus sequence context effects can also be probed. In-house collaboration will be the NMR structural evaluations of the modified duplexes. External collaborations are also planned for UvrABC repair experiments and single molecule studies on protein-DNA complexes. This concerted synthesis and structural evaluation is anticipated to contribute to a greater global understanding of the causative effects in PAH carcinogenesis.

多环芳烃 (PAH) 在环境中普遍存在，对人体构成癌症威胁 人类是现代社会活动的产物。海湾和峡湾地区的多环芳烃交替存在 代谢为 4 种异构二醇环氧化物，它们是有效的 DNA 烷化剂。这些二醇的反应 环氧化物与细胞 DNA 形成 16 种核苷加合物； 8 个异构体 脱氧腺苷 (dA) 和相应的脱氧鸟苷 (dG) 中的 8 个。异构二醇环氧化物具有 显着不同的致瘤性意味着细胞内识别、复制和修复的差异 单个二醇环氧化物-核苷加合物。因此，对结构差异的理解 与生物反应相关的个体二醇环氧化物-DNA损伤有望提供更好的 为在分子水平上了解化学致癌作用奠定了基础。拟议的研究涉及两个 拓扑上不同的结构范式；以苯并[a]芘（BaP）为代表的海湾地区和 以苯并[c]菲 (BcPh) 为代表的峡湾区域，其 DNA 加合物预计会引发 结构特性明显不同。该项目的目标之一是完成小说的描绘， 这两种多环芳烃的所有二醇环氧化物-核苷加合物的明确合成。这样的方法 进化将可能对任何海湾或峡湾地区多环芳烃二醇环氧化物的研究具有普遍适用性。 加合物将被整合到合适的 DNA 序列中（dA 加合物主要是人 N-ras） dG 的 c-Ki-ras）用于在各个序列背景下进行比较研究。其中包括：7m 正常和不匹配互补链的研究，以及温度依赖性 CD 研究 复式公寓。所提出的合成包含足够的灵活性，允许修改任何 序列或在 dG 加合物附近掺入 MeC。因此序列上下文效应也可以 被调查。内部合作将进行改性双链体的核磁共振结构评估。外部的 还计划在 UvrABC 修复实验和蛋白质-DNA 单分子研究方面进行合作 复合物。这种协调一致的综合和结构评估预计将有助于更大的全球范围 了解 PAH 致癌的因果影响。