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(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损伤引起的癌症的病因，DNA损伤是由环境和内源性化学物质产生的，人类人口广泛暴露在这些化学物质中。总体假设是：(1)受损DNA的特定形成对于决定是否修复至关重要；(2)如果修复失败，复制聚合酶中的DNA构象将决定是否发生阻塞、正常或突变旁路；(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，而改变的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)一系列由致癌芳香胺/酰胺衍生的能够进行Watson-Crick配对和堆叠的致癌芳香胺/酰胺，以及(2)无法进行Watson-Crick配对和堆叠的严重扭曲组；这些病变包括来自重要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。具体目标1将确定双链DNA损伤的详细结构和热力学性质，作为加合物结构和导致加合物阻碍复制聚合酶的热力学因素的函数，并描述可能允许Y家族旁路聚合酶中保真度较低的损伤突变或正常旁路的因素。与公众健康的相关性：这项工作将在分子水平上准确定义致癌环境物质产生的含DNA损伤的特定结构和能量特征，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特征。这些研究将促进致癌物损伤DNA的生物监测方面的进展，因为DNA损伤的结构和热力学性质将提供一种区分高度遗传毒性损伤和较良性损伤的方法。