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: 7985925
• 负责人: Suse Broyde
• 金额: $ 30.91万
• 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/7985925
• 关键词: 2-Acetylaminofluorene; Abbreviations; Adenine; Advanced Malignant Neoplasm; Affect; Air; Animals; Aromatic Polycyclic Hydrocarbons; Arts; Attention; Bacillus (bacterium); Base Sequence; Bay Region; Benchmarking; Benzo(a)pyrene; Biological Markers; Breathing; Bypass; Carcinogens; Categories; Cell Extracts; Cells; Characteristics; Chemicals; Chromatin; Chromatin Structure; Chronic; Collaborations; Complex; Complex Mixtures; Counseling; DNA; DNA Adducts; DNA Repair; DNA lesion; Data; Development; Dose; Drug resistance; Early identification; Eating; Environment; Environment and Public Health; Environmental Carcinogens; Enzymes; Epoxy Compounds; Exposure to; Figs - dietary; Food; Future; Generations; Genomics; Glycols; Goals; Guanine; Hand; Histones; Human; Incidence; Individual; Industry; Investigation; Knowledge; Laboratories; Lead; Lesion; Link; Malignant Neoplasms; Measures; Mechanics; Metabolic Activation; Metabolic Pathway; Methods; Modeling; Molecular; Molecular Conformation; Molecular Models; Mutation; Nucleosome Core Particle; Nucleosomes; Nucleotide Excision Repair; Occupational; Organ; Parents; Pathway interactions; Play; Poison; Polymerase; Population; Population Study; Positioning Attribute; Predisposition; Process; Production; Property; Proteins; Publications; Published Comment; Pyrenes; Pyrimidine Dimers; Relative (related person); Reporting; Resistance; Risk; Rodent; Role; Sampling; Screening procedure; Signal Transduction; Site; Smoking; Soot; Source; Structure; System; Temperature; Testing; Therapeutic; Thermodynamics; Time; Tissues; Tobacco; Tobacco smoke; Toxicology; Transcend; Transcription-Coupled Repair; Tumorigenicity; Variant; Work; adduct; base; benzo(c)phenanthrene; benzo(g)chrysene; cancer prevention; chemical carcinogen; chemotherapeutic agent; design; dosage; exposed human population; high risk; innovation; insight; melting; molecular dynamics; molecular modeling; next generation; novel; pollutant; prototype; public health relevance; quantum; repaired; research study; stereochemistry; tool; tumor; tumorigenic

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Our work will advance cancer prevention: it will yield novel capability for efficient screening of polycyclic aromatic hydrocarbons to determine their cancer-initiating potency, and provide next-generation biomarkers for PAH exposure that much better signal cancer susceptibility. In addition, design of more efficacious cancer chemotherapeutic agents will be facilitated.

描述(申请人提供)：一类非平面、扭曲的多环芳烃(PAHs)，被称为Fjord区域化合物，是极强的致癌物质；它们包括二苯并[a，L]芘，它最近被引用为迄今发现的最具致癌活性的多环芳烃。这些污染物作为各种燃料的燃烧产物排放到环境中，并污染粮食作物。它们在食物和城市空气中的低浓度下具有生物活性，对广大人口是危险的。峡湾多环芳烃超乎寻常的致癌能力的来源尚不清楚。然而，最近的研究表明，它们在代谢激活二醇环氧化物后产生的几个笨重的DNA加合物对核苷酸切除修复(NER)具有抵抗力，NER是防止此类DNA损伤的主要细胞防御措施。对这些加合物的DNA修复的抵抗被认为是母体化学物质非凡致瘤性的关键原因，因为它们导致了引发癌症的突变。然而，每个环境峡湾多环芳烃都会产生一种立体异构体鸟嘌呤和腺嘌呤DNA加合物的复杂混合物。此外，每个加合物的NER敏感性可能随着DNA碱基序列的不同而不同。在这众多的病变中，导致癌症的关键修复抵抗病变仍未确定。我们广泛而长期的目标是，与我们的实验合作者N.Geacintov教授合作，使用创新和最先进的建模方法来鉴定耐纳加合物及其特征：我们假设耐纳加合物由多环芳烃修饰的DNA的结构、动力学和热力学性质决定。我们选择了二苯并[a，L]芘、苯并[g]黄森和苯并[c]菲作为详细研究对象，研究了它们通过已建立的二醇环氧化物代谢活化途径生成的加合物。这些多环芳烃分别代表6环、5环和4环的芳香族体系，这是诱导肿瘤的最佳范围。我们的目标是研究三个母体多环芳烃在选定的序列中的许多二醇环氧化物加合物，我们假设这些加合物将改变它们的NER敏感性。我们进一步的目标是确定病变的特征属性和NER易感性，当组织在核小体的组蛋白蛋白环境中时，核小体是细胞环境中染色质结构的基本单位。这是在染色质背景下阐明复杂的NER机制功能的关键的第一步。我们将与我们的实验合作者N.Geacintov教授携手合作：NER数据与人类细胞提取物和包括含有病变的核小体的数据将提供将我们的发现与实验观察直接联系起来的锚，我们的分析将指向将在他的实验室进行测试的重要预测。我们的研究将提供暴露于多环芳烃的下一代生物标志物，通过我们对NER机制的了解，促进设计更好的耐NER化疗药物，并提高我们对环境中存在的多环芳烃加合物进行遗传毒性筛选的能力。 公共卫生相关性：我们的工作将推进癌症预防：它将产生有效筛选多环芳烃以确定其致癌效力的新能力，并提供多环芳烃暴露的下一代生物标记物，更好地指示癌症易感性。此外，还将促进更有效的癌症化疗药物的设计。