DNA Lesion Structures: Mutagenicity and Repair

DNA 损伤结构：致突变性和修复

• 批准号: 7634396
• 负责人: Suse Broyde
• 金额: $ 28.44万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7634396
• 关键词: 2-Acetylaminofluorene; 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine; 2-aminofluorene; 4-biphenylamine; Active Sites; Adenine; Affect; Amides; Amines; Aromatic Amines; Automobile Exhaust; Bacillus (bacterium); Base Excision Repairs; Base Sequence; Benign; Biological; Biological Monitoring; Bypass; Carcinogens; Cells; Characteristics; Chemicals; Collaborations; Complex; Cytosine; DNA; DNA Adducts; DNA Damage; DNA Polymerase I; DNA Repair; DNA lesion; DNA-Directed DNA Polymerase; Data; Dependence; Elements; Equilenin; Equilibrium; Etiology; Eukaryota; Excision; Family; Figs - dietary; Food; Foundations; Gene Mutation; Genetic; Goals; Guanine; Hormones; Human; Hydrogen Bonding; Induced Mutation; Laboratories; Lesion; Link; Malignant Neoplasms; Metabolic; Methods; Minor; Modeling; Modification; Molecular; Molecular Conformation; Motivation; Mutagenesis; Mutation; Nucleotide Excision Repair; Nucleotides; Pathway interactions; Pharmaceutical Preparations; Polymerase; Population; Predisposition; Primer Extension; Probability; Process; Prokaryotic Cells; Property; Public Health; Purines; Reactive Oxygen Species; Research; Series; Staging; Stereoisomer; Structure; System; Testing; Thermodynamics; Time; Tobacco smoke; Variant; Work; adduct; base; cancer initiation; chemical carcinogen; conformer; cooking; hazard; member; novel; oxidation; prevent; professor; purine; pyridine; repaired; stereochemistry

DESCRIPTION (provided by applicant): The broad and long term goals of this research is to determine on a molecular level the etiology of cancer initiation by DNA damage, produced by environmental and endogenous chemicals to which the human population is widely exposed. The overall hypotheses are: (1) The specific formation of damaged DNA is critical in determining if it is repaired or not; (2) if repair fails, the DNA conformation within a replicative polymerase determines whether blockage, normal or mutagenic bypass occurs; (3) if normal replication is impeded, then the altered DNA will encounter one or more bypass polymerases, and the specific conformation of the altered DNA will determine whether a mutation which may initiate cancer occurs. The PI will test these hypotheses by determining structural, dynamic and thermodynamic properties for two groups of lesions: (1) a series derived from carcinogenic aromatic amines/amide presenting tobacco smoke, automobile exhaust and cooked foods that are capable of Watson-Crick pairing and stacking, and (2) a severely distorting group incapable of Watson-Crick pairing, with impaired stacking; these include a lesion derived from a prominent hormone replacement drug, and one produced by endogenous and exogenous reactive oxygen species. Specific aim 1 will determine detailed structural and thermodynamic properties of the lesions in duplex DNA as a function of adduct structure and thermodynamic factors that cause the adducts to impede replicative polymerases, and to delineate factors which could permit mutagenic or normal bypass of the lesions with lowered fidelity in Y-family bypass polymerases. Relevance to public health: this work will define precisely on a molecular level, the specific structural and energetic characteristics of DNA-containing lesions derived from carcinogenic environmental substances, and thus provided the molecular hallmarks that distinguish very harmful chemicals from benign ones. These studies will facilitate advances in biomonitoring of carcinogen - damaged DNA, since the structural and thermodynamic properties of the DNA lesions would provide a method for distinguishing highly genotoxic lesions from more benign ones.

描述（由申请人提供）：本研究的广泛和长期目标是在分子水平上确定由DNA损伤引发癌症的病因学，DNA损伤由人类广泛暴露的环境和内源性化学物质产生。总体假设为：（1）受损DNA的特异性形成在确定其是否被修复方面是关键的;（2）如果修复失败，复制聚合酶内的DNA构象决定是否发生阻断、正常或诱变旁路;（3）如果正常复制受阻，则改变的DNA将遇到一个或多个旁路聚合酶，改变的DNA的特定构象将决定是否发生可能引发癌症的突变。PI将通过确定两组病变的结构、动力学和热力学性质来检验这些假设：（1）一系列来源于致癌芳香胺/酰胺，表现为烟草烟雾、汽车尾气和熟食，能够进行沃森-克里克配对和堆叠，以及（2）严重扭曲的组，不能进行沃森-克里克配对，堆叠受损;这些疾病包括由主要激素替代药物引起的病变，以及由内源性和外源性活性氧物质引起的病变。具体目标1将确定作为加合物结构和热力学因素的函数的双链体DNA中的病变的详细结构和热力学性质，所述加合物结构和热力学因素导致加合物阻碍复制聚合酶，并且描绘可以允许Y家族旁路聚合酶中保真度降低的病变的诱变或正常旁路的因素。与公共卫生的相关性：这项工作将在分子水平上精确地确定致癌环境物质引起的含DNA病变的具体结构和能量特征，从而提供区分非常有害的化学物质和良性化学物质的分子标志。这些研究将促进致癌物损伤DNA的生物监测的进展，因为DNA损伤的结构和热力学性质将提供一种区分高遗传毒性损伤与更良性损伤的方法。