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

致癌物-DNA 加合物：拓扑、构象和修复（更新）

基本信息

批准号：
8677691
负责人：
Suse Broyde
金额：
$ 29.77万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1981
资助国家：
美国
起止时间：
1981-04-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8677691
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

项目摘要

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.

一类非平面扭曲多环芳烃 (PAH)，称为峡湾地区化合物，是极强的致瘤剂；它们包括最近被引用的二苯并[a,l]芘是迄今为止发现的最具致瘤性的多环芳烃。这些污染物随着燃烧释放到环境中各种燃料的产品，并污染粮食作物。它们在低水平下具有生物活性食品和城市空气中存在的浓度对广大人群有害。的起源峡湾多环芳烃的非凡致癌效力仍不清楚。然而最近却被曝光它们在代谢活化为二醇环氧化物后产生的一些大体积 DNA 加合物是对核苷酸切除修复 (NER) 具有抵抗力，这是针对此类 DNA 损伤的主要细胞防御机制。这些加合物对 DNA 修复的抵抗被认为是导致非同寻常的致瘤性的关键原因。母体化学物质，因为它们会引起引发癌症的突变。然而，每个环境峡湾 PAH 产生立体异构鸟嘌呤和腺嘌呤 DNA 加合物的复杂混合物。此外，每个此类加合物的 NER 敏感性可能随 DNA 碱基序列的不同而变化。在这众多的病变中，关键是导致癌症的抗修复基因仍未被识别。我们广泛的长期目标是，致力于与我们的实验合作者 N. Geacintov 教授合作，鉴定 NER 抗性加合物及其使用创新和最先进的建模方法来研究特征：我们假设 NER 抗性是受 PAH 修饰 DNA 的结构、动力学和热力学特性控制。峡湾多环芳烃选择进行详细研究的是二苯并[a,l]芘、苯并[g]屈和苯并[c]菲；我们研究它们通过完善的二醇环氧化物代谢激活途径产生的加合物。这些 PAH 分别代表 6、5 和 4 环芳香族系统，这是诱导肿瘤的最佳范围。我们的目的是研究我们选定的序列中三种母体 PAH 的许多二醇环氧化物加合物。假设会改变他们的 NER 敏感性。我们进一步的目标是确定特征属性和当在核小体的组蛋白环境中组织时，损伤的 NER 敏感性，细胞环境中染色质结构的基本单位。这是阐明问题的重要第一步染色质背景下复杂的 NER 机制的功能。我们将与我们的合作伙伴携手并进实验合作者 N. Geacintov 教授：人体细胞提取物的 NER 数据，包括病变- 含有核小体将为我们的发现与实验直接联系起来提供锚点观察，我们的分析将指出重要的预测，并将在他的实验室中进行测试。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 NER- 通过我们对 NER 机制的了解，我们可以发现耐药化疗药物，并推进我们的研究能够对我们环境中存在的 PAH 衍生的加合物进行基因毒性筛查。