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: 7231305
• 负责人: MAHESH K LAKSHMAN
• 金额: $ 16.44万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231305
• 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(PAHs)广泛存在于环境中，对人体健康构成致癌威胁。 人类是现代社会活动的产物。交替的海湾和峡湾地区的PAHs是 代谢成4个同分异构体的二醇环氧化物，是有效的DNA烷基化试剂。这些二元醇的反应 环氧化物与细胞DNA形成16个核苷加合物；8个异构体来自 脱氧腺苷(Da)和相应的8脱氧鸟苷(Dg)。同分异构体二醇环氧化物具有 明显不同的致瘤性意味着细胞内识别、复制和修复的差异 单独的二元醇环氧化物-核苷加合物。因此，理解两国之间的结构性差异 个别二醇环氧化物-DNA损伤的生物学反应有望提供更好的 从分子水平上理解化学致癌的基础。建议进行的研究有两项 拓扑上不同的结构范例；海湾地区以苯并[a]芘(BaP)和 以苯并[c]菲(BcPh)为代表的峡区，其DNA加合物有望诱导 明显不同的结构特性。该项目的目标之一是完成小说的描绘， 明确合成了这两种多环芳烃的所有二醇环氧化物-核苷加合物。实现这一目标的方法 Evolve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。 加合物将被结合到合适的DNA序列中(主要是用于da加合物的人N-ras 和c-ki-ras用于DG)，用于在各个序列上下文中进行比较研究。其中包括：700万 正常和错配互补链的研究，以及依赖温度的CD研究 双面的。拟议的合成包含了足够的灵活性，以允许修改任何 序列或与DG加合物相邻的MEC的掺入。因此，序列上下文效应还可以 被调查。内部合作将对修饰的双链进行核磁共振结构评估。外部 还计划在UvrABC修复实验和蛋白质-DNA的单分子研究方面进行合作 复合体。这一协调一致的综合和结构评估预计将有助于更大的全球 对多环芳烃致癌作用的理解。