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

• 批准号: 8856568
• 负责人: LAURIE G HUDSON
• 金额: $ 33.98万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856568
• 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

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（由适用提供）：通过饮用水的宽度宽度超过环境保护局和世界卫生组织的水平，最低污染物水平为10'g/l是国家和国际上的关注点。越来越多的人越来越多地认为，砷的低和非毒性浓度可以扩大其他遗传毒性剂（例如紫外线辐射）的DNA损伤和致癌潜力，至少部分通过抑制DNA修复过程。砷抑制DNA修复靶蛋白的机制对于理解砷的致癌和共同致癌潜力至关重要，并确定途径以逆转或防止人群中砷暴露的不利影响。当前的项目将检验以下假设：砷生成的活性氧和氮种通过与氧化还原敏感的半胱氨酸保留锌指域抑制锌指DNA修复蛋白的活性。在AIM 1中，我们将研究砷介导的INOS和NADPH氧化物（NOX）诱导以及随后的一氧化氮和超氧化物的产生对两种DNA修复蛋白（XPA和PARP-1），DNA修复和遗传毒性的活性。 iNOS和NOX的遗传和药物破坏将定义哪些途径参与砷介导的DNA修复抑制。 AIM 2将研究砷生成的活性氧和氮种与XPA和PARP-1的锌指的相互作用，并应用分析技术来定义锌指域的特定修饰，以及对锌结合的后果。 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.在AIM 3中，我们将使用遗传模型在DNA损伤和紫外线辐射之间在DNA损伤和皮肤肿瘤发生中报告的INOS和NOX依赖性。这是该项目严格测试使用多方面方法对关键DNA修复靶蛋白砷抑制的机制。这些研究的结果将提高我们对锌指DNA修复蛋白功能的砷破坏机制的理解，并可能对砷暴露群体的治疗或预防干预措施产生重大影响。此外，这些研究可能导致有关癌症和其他砷相关疾病的潜在砷靶标的可检验的假设。