Excision of Environmental Carcinogen-DNA Lesions by Human NER enzymes

人类 NER 酶切除环境致癌物 DNA 损伤

基本信息

批准号：
7538319
负责人：
Nicholas E Geacintov
金额：
$ 32.75万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7538319
关键词：
4-biphenylamine Adenine Adopted Air Animals Aromatic Amines Aromatic Polycyclic Hydrocarbons Base Sequence Bay Region Benzo(a)pyrene Binding Biological Markers Biological Models Breathing Bypass Cancer Etiology Carcinogens Cations Cells Characteristics Chemical Structure Chemicals Classification Coal Cytochrome P450 DNA DNA Adducts DNA Damage DNA Repair DNA biosynthesis DNA lesion Defense Mechanisms Development Disease Distant Elderly Environment Environmental Carcinogens Epoxy Compounds Etiology Excision Exposure to Family Figs - dietary Fishes Food Fossil Fuels Free Radicals Genetic Polymorphism Glycols Guanine Health Heating Human Human body Individual Ingestion Investigation Lead Lesion Life Lung Malignant Neoplasms Meat Mediating Metabolic Activation Methods Modeling Molecular Molecular Conformation Monitor Mutagens Mutation Nucleotide Excision Repair Outcome Oxidation-Reduction Oxidoreductase Pathway interactions Pattern Play Population Positioning Attribute Predisposition Problem Solving Process Progress Reports Property Proteins Protocols documentation Pyrenes Quinones Reaction Reporting Research Project Grants Resistance Risk Role Side Site Staging Structure Thermodynamics Tobacco smoke Variant World Health Organization adduct amino group base benzo(c)phenanthrene carcinogenesis cigarette smoking cooking design ds-DNA enantiomer environment related cancer exposed human population hazard heterocyclic aromatic amines human DNA damage nucleobase oxidation oxidative DNA damage pollutant prevent pyridine repair enzyme repaired response success tool working group

项目摘要

DESCRIPTION (provided by applicant): Exposure of the human population to cancer-causing substances in the environment constitutes an important hazard to human health. Among these chemicals are polycyclic aromatic hydrocarbons in urban polluted environments and in cigarette smoke, and aromatic amines mutagens present in cooked foods. These chemicals, once they enter the human body, are activated to highly reactive intermediates that chemically bind to DNA, thus generating bulky adducts. The latter, if not removed by cellular defense mechanisms, can cause mutations and cancer. One of the critical lines of defense of the human body to these environmental carcinogens is DNA repair, specifically by the nucleotide excision repair (NER) mechanism that deals with bulky DNA damage. Unfortunately, the molecule basis of this critical defense mechanism, especially its efficiency in removing important, structurally different DNA lesions, is still obscure. In this project, a systematic approach towards solving this problem is proposed that will identify the kind of carcinogen-DNA lesions that are poorly repaired by NER mechanisms. This information will be useful in biomarker studies of environmental human exposure, and will be especially useful for identifying individuals who, because of genetic polymorphisms, are of particular risk of developing cancer. Such individuals can then be selected for closer monitoring to prevent the development of this disease into tits later life-threatening stages.

描述（由申请人提供）：人类暴露于环境中的致癌物质对人类健康构成重要危害。这些化学物质包括城市污染环境和香烟烟雾中的多环芳烃，以及熟食中存在的芳香胺诱变剂。这些化学物质一旦进入人体，就会被激活为高反应性中间体，与 DNA 发生化学结合，从而产生大量的加合物。后者如果不被细胞防御机制消除，可能会导致突变和癌症。人体抵御这些环境致癌物的关键防线之一是 DNA 修复，特别是通过处理大量 DNA 损伤的核苷酸切除修复 (NER) 机制。不幸的是，这种关键防御机制的分子基础，尤其是其去除重要的、结构不同的 DNA 损伤的效率，仍然不清楚。在这个项目中，提出了一种解决这一问题的系统方法，该方法将识别 NER 机制修复效果不佳的致癌物质 DNA 损伤的类型。这些信息将有助于人类环境暴露的生物标志物研究，并且对于识别由于遗传多态性而具有患癌症特定风险的个体尤其有用。然后可以选择这些个体进行更密切的监测，以防止这种疾病发展到后来危及生命的阶段。