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）：这项研究的广泛和长期目标是在分子水平上确定由DNA损伤开始的癌症开始的病因，这是由环境和内源性化学物质所产生的，人口被广泛暴露于该化学物质。总体假设是：（1）受损DNA的特定形成对于确定是否修复至关重要； （2）如果修复失败，复制性聚合酶内的DNA构象决定阻塞，正常还是诱变旁路发生； （3）如果阻碍了正常的复制，则改变的DNA会遇到一个或多个旁路聚合酶，并且改变的DNA的特定构象将确定是否会发生癌症的突变。 PI将通过确定两组病变的结构，动态和热力学特性来检验这些假设：（1）源自致癌芳香胺/酰胺的一系列散发烟草烟雾，汽车排气和煮熟的食物，这些食物能够与watson-crick crick crick搭配和（2）杂乱无章的组合，以及（2）杂乱无章的组合 - 这些包括源自突出的激素替代药物的病变，以及由内源性和外源性活性氧产生的病变。具体的目标1将确定双链DNA病变的详细结构和热力学特性，这是加合物结构和热力学因素的函数，这些因素会导致加合物阻碍复制性聚合酶，并揭示可以允许刺激性或正常绕过y型屈曲度的病变的因素，从而削减了延误的屈服。与公共卫生的相关性：这项工作将准确地定义在分子水平，这是源自致癌环境物质的含DNA的特定结构和能量特征，因此提供了将非常有害化学物质与良性化学物质区分开的分子标志。这些研究将促进致癌物受损的DNA生物监测的进展，因为DNA病变的结构和热力学特性将提供一种将高度遗传毒性病变与更良性的方法区分开的方法。