Arsenic co-carcinogenesis with UVR: nitrosation and oxidation of target proteins

砷与 UVR 的协同致癌作用：目标蛋白的亚硝化和氧化

基本信息

批准号：
8537458
负责人：
LAURIE G HUDSON
金额：
$ 33.3万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8537458
关键词：
Address Adverse effects Animal Model Area Arsenic Arsenites Binding Biochemical Biological Models Carcinogens Cells Chemicals Cysteine DNA Binding DNA Damage DNA Repair DNA Repair Inhibition DNA repair protein Data Dependence Disease Elements Exposure to Food Frequencies Generations Genetic Genetic Models Goals Health Hormone Receptor DNA-Binding Domain Human Individual International Intervention Knowledge Laboratories Lead Life Style Light Link Liver Malignant Neoplasms Malignant neoplasm of lung Mediating Modification Molecular Mutagens Mutation NADPH Oxidase Nitric Oxide Nitrogen Nitrosation Occupational Outcome Study Oxidation-Reduction Oxidative Stress Oxygen Pathway interactions Peptides Play Poly(ADP-ribose) Polymerases Population Process Proteins Reaction Reporting Risk Factors Role Skin Skin Cancer Soil Specificity Structure Superoxides Techniques Testing Time Toxic effect Translating UV induced Ultraviolet Rays United States United States Environmental Protection Agency Urinary tract Water Water Supply World Health Organization Xeroderma Pigmentosum Zinc Zinc Fingers arm base cancer risk carcinogenesis drinking water exposed human population genotoxicity improved in vivo inhibitor/antagonist interest keratinocyte nitrosative stress oxidation oxidative damage prevent protein function prototype repaired research study synergism tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Widespread human exposure to arsenic through drinking water at levels in excess of the Environmental Protection Agency and World Health Organization minimum contaminant level of 10 ¿g/L is a national and international concern. It is becoming increasingly appreciated that low and non-cytotoxic concentrations of arsenic can amplify the DNA damaging and carcinogenic potential of other genotoxic agents such as ultraviolet radiation, at least in part, through inhibition of DNA repair processes. The mechanisms by which arsenic inhibits DNA repair target proteins is central to understanding the carcinogenic and co-carcinogenic potential of arsenic and to identify avenues to reverse or prevent the adverse effects of arsenic exposure in human populations. The current project will test the hypothesis that arsenic-generated reactive oxygen and nitrogen species inhibits the activity of zinc finger DNA repair proteins through reaction with redox-sensitive cysteine residues of the zinc finger domains. In Aim 1 we will investigate the impact of arsenic-mediated iNOS and NADPH oxidase (NOX) induction and subsequent nitric oxide and superoxide generation on the activity of two DNA repair proteins (XPA and PARP-1), DNA repair and genotoxicity in keratinocytes. Genetic and pharmacologic disruption of iNOS and NOX will define which pathway(s) are involved in arsenic-mediated inhibition of DNA repair. Aim 2 will investigate the interaction of arsenic-generated reactive oxygen and nitrogen species with the zinc fingers of XPA and PARP-1 and apply analytical techniques to define specific modifications of the zinc finger domain and consequences with regard to zinc binding. Data generated by our laboratories and others indicate selectivity for arsenic binding to zinc finger structures and we find that arsenic- bound, but not zinc bound, zinc finger peptide is highly vulnerable to oxidation We will test whether arsenic binding to a zinc finger translates to targeted oxidative and nitrosative modification and loss of zinc finger protein function. In Aim 3, we will test the iNOS and NOX dependence for the reported synergism between arsenic and ultraviolet radiation in DNA damage and skin tumorigenesis in vivo using genetic models. Thus, this project rigorously tests mechanisms of arsenic inhibition of key DNA repair target proteins using a multi- faceted approach. The outcomes from these studies will improve our understanding of mechanisms underlying arsenic disruption of zinc finger DNA repair protein function and may have significant impact on treatments or preventative interventions for arsenic exposed populations. Additionally, these studies may lead to testable hypotheses regarding potential arsenic targets in cancer and other arsenic-associated diseases.

描述（由申请人提供）：人类通过饮用水广泛接触砷，砷含量超过环境保护署和世界卫生组织规定的最低污染物含量 10 ¿ g/L 是一个国家和国际关注的问题，人们越来越认识到低浓度和非细胞毒性的砷可以通过抑制 DNA 来放大其他遗传毒性物质（例如紫外线）的 DNA 损伤和致癌潜力。砷抑制 DNA 修复靶蛋白的机制对于了解砷的致癌和共致癌潜力以及确定逆转或预防其不利影响的途径至关重要。当前的项目将测试砷产生的活性氧和氮物质通过与锌指结构域的氧化还原敏感的半胱氨酸残基反应来抑制锌指 DNA 修复蛋白的活性的假设。我们将研究砷介导的 iNOS 和 NADPH 氧化酶 (NOX) 诱导以及随后的一氧化氮和超氧化物生成对两种 DNA 修复蛋白（XPA 和PARP-1)、角质形成细胞中的 DNA 修复和遗传毒性。iNOS 和 NOX 的遗传和药理学破坏将确定哪些途径参与砷介导的 DNA 修复抑制。目标 2 将研究砷产生的活性氧的相互作用。我们的实验室和其他实验室生成的数据表明，XPA 和 PARP-1 的锌指具有氮物种，并应用分析技术来定义锌指结构域的具体修饰以及锌结合的后果。砷与锌指结构结合的选择性，我们发现与砷结合但不与锌结合的锌指肽非常容易氧化。我们将测试砷与锌指的结合是否会转化为有针对性的氧化和亚硝化修饰以及锌的损失在目标 3 中，我们将测试 iNOS 和 NOX 依赖性，以了解砷和紫外线辐射在 DNA 损伤和皮肤肿瘤发生中的协同作用。因此，该项目使用多方面的方法严格测试砷抑制关键 DNA 修复靶蛋白的机制，这些研究的结果将提高我们对砷破坏锌指 DNA 修复蛋白功能的机制的理解。并可能对砷暴露人群的治疗或预防干预产生重大影响。此外，这些研究可能会得出关于癌症和其他砷相关疾病的潜在砷目标的可检验假设。