Carcinogen-DNA Adducts: Topology, Conformation and Repair (Renewal)

致癌物-DNA 加合物：拓扑、构象和修复（更新）

• 批准号: 8461152
• 负责人: Suse Broyde
• 金额: $ 28.84万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-04-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461152
• 关键词: Adenine; Advanced Malignant Neoplasm; Affect; Air; Animals; Aromatic Polycyclic Hydrocarbons; Attention; Base Sequence; Bay Region; Benchmarking; Benzo(a)pyrene; Biological Markers; Breathing; Bypass; Carcinogens; Categories; Cell Extracts; Characteristics; Chemicals; Chromatin; Chromatin Structure; Chronic; Complex; Complex Mixtures; DNA; DNA Adducts; DNA Repair; DNA lesion; Data; Dose; Eating; Environment; Environmental Carcinogens; Enzymes; Epoxy Compounds; Food; Glycols; Goals; Guanine; Histones; Human; Industry; Investigation; Laboratories; Lead; Lesion; Link; Malignant Neoplasms; Measures; Metabolic Activation; Metabolic Pathway; Methods; Modeling; Molecular Conformation; Molecular Models; Mutation; Nucleosome Core Particle; Nucleosomes; Nucleotide Excision Repair; Occupational; Organ; Parents; Pathway interactions; Play; Polymerase; Population; Predisposition; Process; Property; Proteins; Pyrenes; Relative (related person); Reporting; Resistance; Risk; Role; Sampling; Signal Transduction; Site; Smoking; Soot; Structure; System; Temperature; Testing; Thermodynamics; Time; Tumorigenicity; Variant; Work; adduct; base; benzo(c)phenanthrene; benzo(g)chrysene; cancer prevention; chemical carcinogen; chemotherapeutic agent; cold temperature; design; dosage; innovation; melting; molecular modeling; next generation; novel; pollutant; prototype; repaired; screening; stereochemistry; tool; tumor; tumorigenic

A category of non-planar, twisted polycyclic aromatic hydrocarbons (PAHs), termed fjord region compounds, are extremely potent tumorigens; they include dibenzo[a,l]pyrene which has recently been cited as the most tumorigenic PAH yet identified. These pollutants are released into the environment as combustion products of a variety of fuels, and they contaminate food crops. They are biologically active at the low concentrations present in foods and urban air and are hazardous to the population at large. The origin of the extraordinary carcinogenic potencies of fjord PAHs remains unknown. However, it has recently been shown that several of the bulky DNA adducts that they produce after metabolic activation to diol epoxides, are resistant to nucleotide excision repair (NER), the principal cellular defense against such DNA lesions. Resistance to DNA repair of these adducts is deemed a critical cause for the extraordinary tumorigenicity of the parent chemicals, as they cause the mutations which initiate cancer. However, each environmental fjord PAH gives rise to a complex mixture of stereoisomeric guanine and adenine DNA adducts. Furthermore, the NER susceptibility of each such adduct may vary with DNA base sequence. In this multitude of lesions, the key repair-resistant ones that lead to cancer remain unidentified. Our broad, long-term objective is, working in tandem with our experimental collaborator Prof. N. Geacintov, to identify the NER-resistant adducts and their characteristics using innovative and state-of-the-art modeling methods: we hypothesize that NER-resistance is governed by the structural, dynamic and thermodynamic properties of the PAH-modified DNA. The fjord PAHs selected for detailed study are dibenzo[a,l]pyrene, benzo[g]chrysene, and benzo[c]phenanthrene; we investigate their adducts produced via the well established diol epoxide metabolic activation pathway. These PAHs represent aromatic systems of 6, 5, and 4 rings, respectively, a range optimal for the induction of tumors. We aim to investigate the many diol epoxide adducts of the three parent PAHs in selected sequences that we hypothesize will alter their NER-susceptibilities. We further aim to determine the characteristic properties and NER susceptibilities of lesions when organized within the histone protein environment of the nucleosome, the basic unit of chromatin structure in the cellular environment. This is an essential first step towards elucidating the functioning of the complex NER machinery in the context of chromatin. We will work hand-in-hand with our experimental collaborator Prof. N. Geacintov: NER data with human cell extracts and including lesion- containing nucleosomes will provide anchors for directly linking our findings with the experimental observations, and our analyses will point to important predictions that will be tested in his laboratory. Our studies will provide the next-generation of biomarkers for PAH exposure, facilitate design of better NER- resistant chemotherapeutics through our gained understanding of NER mechanisms, and advance our capability for genotoxic screening of adducts derived from PAHs present in our environment.

一类非平面，扭曲的多环芳烃（PAHS）称为峡湾区域 化合物是极有效的肿瘤剂；它们包括最近引用的dibenzo [a，l] pyrene 正如尚未确定的最肿瘤的PAH。这些污染物被释放到环境中 各种燃料的产品，它们污染了粮食作物。它们在低的生物学上活跃 食品和城市空气中存在的浓度，对整个人口危害。起源于 峡湾PAH的非凡致癌效力仍然未知。但是，最近已显示 它们在代谢环氧化物的代谢激活后产生的几种笨重的DNA加合物是 对核苷酸切除修复（NER）的耐药性，这是针对此类DNA病变的主要细胞防御。 对这些加合物的DNA修复的抗性被认为是特殊肿瘤性的关键原因 母体化学物质，因为它们引起了引发癌症的突变。但是，每个环境峡湾 PAH产生了立体异构体鸟嘌呤和腺嘌呤DNA加合物的复杂混合物。此外， 每种这种加合物的NER敏感性可能随DNA碱基序列而变化。在众多病变中，钥匙 导致癌症的维修耐药性仍然不明。我们广泛的长期目标是 与我们的实验合作者N. Gecintov教授相连，以识别耐Ner的加合物及其 使用创新和最先进的建模方法的特征：我们假设NER抗性是 由PAH修饰的DNA的结构，动态和热力学特性约束。峡湾PAH 选择进行详细研究的是Dibenzo [A，L] Pyrene，Benzo [G] Chrysene和Benzo [C]稳定；我们 研究它们通过良好的二醇环氧代谢激活途径产生的加合物。这些 PAHS分别代表6、5和4环的芳族系统，是肿瘤诱导的最佳范围。 我们旨在研究我们的三个母体PAH的许多二醇环氧加合物，以我们的选定序列 假设将改变其NER的自由度。我们进一步旨在确定特征性能和 当在核小体的组蛋白蛋白环境中组织病变的NER敏感性， 细胞环境中染色质结构的基本单位。这是阐明的重要第一步 复杂的NER机械在染色质的情况下的功能。我们将与我们的 实验合作者N. Gecintov教授：具有人类细胞提取物的NER数据，包括病变 - 含有核小体将为直接联系我们的发现与实验性提供锚点 观察结果，我们的分析将指出将在其实验室中测试的重要预测。我们的 研究将为PAH暴露提供下一代生物标志物，促进设计更好的设计 通过我们对NER机制的了解，抗性化学治疗剂，并促进我们的 源自环境中存在的PAH的加合物的遗传毒性筛选的能力。