Environmental Carcinogen-DNA Adducts: NER Recognition

环境致癌物-DNA 加合物：NER 识别

• 批准号: 9275988
• 负责人: Suse Broyde
• 金额: $ 35.66万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275988
• 关键词: Abate; Advanced Malignant Neoplasm; Airborne Particulate Matter; Aromatic Compounds; Benchmarking; Binding; Biological Markers; Biological Monitoring; Cancer Etiology; Cells; Characteristics; Chemicals; Complex; Crystallization; DNA; DNA Adducts; DNA Damage; DNA Library; DNA Sequence; DNA lesion; Defense Mechanisms; Dependence; Development; Disease; Environment; Environmental Carcinogens; Environmental Exposure; Environmental Pollutants; Environmental Pollution; Equilibrium; Etiology; Exposure to; Food; Fossil Fuels; Free Energy; Funding; Health; Histones; Human; Human Genome; Impairment; Individual; Inflammation; Inflammatory Response; Lead; Lesion; Libraries; Malignant - descriptor; Malignant Neoplasms; Methods; Molecular; Mutation; Nucleosomes; Nucleotide Excision Repair; Orthologous Gene; Oxides; Pathway interactions; Pharmaceutical Preparations; Policies; Predisposition; Property; Proteins; Pyrimidine Dimers; RAD23B gene; Recruitment Activity; Repair Complex; Resistance; Risk; Role; Signal Transduction; Site; Skin; Structure; Sunlight; Testing; Thermodynamics; Tobacco; Tobacco smoke; Ultraviolet Rays; Water; Work; Xeroderma Pigmentosum; Yeasts; base; cancer prevention; carcinogenesis; carcinogenicity; chemical carcinogen; chemotherapeutic agent; design; exhaust; exposed human population; gene repair; genotoxicity; human disease; human tissue; insight; next generation; novel; public health relevance; repaired; screening; superfund site; ultraviolet; wasting

 DESCRIPTION (provided by applicant): The human genome is under constant attack from environmental pollutants, endogenous reactive oxidizing species that are secreted in human tissues during the inflammatory response, and ultraviolet components of sunlight. Among the exogenous cancer-causing environmental contaminants are polycyclic aromatic compounds that are byproducts of fossil fuel combustion found at toxic waste dumps and superfund sites, in airborne particulates, and in our food and water. The DNA lesions derived from polycyclic aromatic compounds, inflammation-related reactive oxidizing species, and ultraviolet light result in the accumulation of malignant mutations that lead to a variety of human cancers. However, not all DNA lesions are equally effective in promoting human diseases: while lesions can be excised by the human nucleotide excision repair (NER) mechanism, some DNA lesions are rapidly repaired, some are repaired slowly, and some are entirely resistant to NER and are therefore particularly genotoxic. The vital importance of NER is demonstrated in the devastating human disorder xeroderma pigmentosum, caused by mutations in various NER genes. However, why certain DNA lesions are NER-resistant and others are not when NER is normal, is not understood. The objective of this project is to provide mechanistic insights into this puzzling variability of DNA lesion repair, by focusing on the key step of lesion recognition in NER, to yield a molecular understanding of NER resistance. We hypothesize that how well a lesion is recognized is determined by the extent of destabilization or stabilization that it impose on DNA: stabilization leads to repair resistance and destabilization facilitates repair. We will dissect the structural, dynamic and thermodynamic properties for a selected set of DNA lesions that govern whether they are recognized by Rad4-Rad23, the yeast ortholog of the human XPC-RAD23B lesion recognition factor. In Aim 1 we will determine the extent that local thermodynamic stability of lesion-containing DNA regulates their recognition. In Aim 2 we will determine the molecular mechanism for productive binding of Rad4-Rad23 that successfully recognizes the lesions and correctly recruits subsequent NER factors, and how the binding pathway and free energies along this pathway depend on lesion structures. In Aim 3 we will investigate DNA complexed with histone proteins in nucleosomes, the fundamental packaging unit of DNA in cells. We will determine how access of the NER proteins to DNA lesions in nucleosomes is governed by the lesion's structural and dynamic properties to promote or inhibit repair. The novel insights into the DNA lesion recognition mechanisms of NER that we will gain may lead to the development of more effective, less NER- susceptible chemotherapeutic agents, since the efficacy of current drugs is impaired by NER. Furthermore, such understanding will help to identify the most genotoxic cancer-causing precursors among the many environmental contaminants, thus allowing for the development of better targeted abatement policies and biomonitoring methods of the associated health risks.

 描述（由申请人提供）：人类基因组不断受到环境污染物、炎症反应期间人体组织中分泌的内源性活性氧化物质以及阳光紫外线成分的攻击。在外源性致癌环境污染物中，有多环芳香族化合物，它们是化石燃料燃烧的副产品，存在于有毒废物倾倒场和超级基金场地、空气中的颗粒物以及我们的食物和水中。来自多环芳香族化合物、炎症相关的活性氧化物质和紫外线的DNA损伤导致恶性突变的积累，从而导致各种人类癌症。然而，并非所有的DNA损伤在促进人类疾病方面都同样有效：虽然损伤可以通过人类核苷酸切除修复（NER）机制切除，但一些DNA损伤可以快速修复，一些修复缓慢，而一些则完全抵抗NER，因此具有特别的遗传毒性。NER的至关重要性在由各种NER基因突变引起的毁灭性人类疾病着色性干皮病中得到证明。然而，为什么某些DNA损伤是NER抗性的，而其他DNA损伤在NER正常时不是，尚不清楚。该项目的目标是通过关注NER中损伤识别的关键步骤，为DNA损伤修复的这种令人困惑的变异性提供机制见解，以获得对NER抗性的分子理解。 我们假设，如何识别病变是由它对DNA施加的不稳定或稳定的程度决定的：稳定导致修复阻力和不稳定促进修复。我们将解剖的结构，动力学和热力学性质的一组选定的DNA病变，管理他们是否被认可的Rad 4-Rad 23，酵母直系同源的人XPC-RAD 23 B病变识别因子。在目标1中，我们将确定的程度，局部热力学稳定的病变含有DNA调节其识别。在目标2中，我们将确定Rad 4-Rad 23的有效结合的分子机制，其成功地识别病变并正确地募集随后的NER因子，以及结合途径和自由能沿着该途径如何取决于病变结构。在目标3中，我们将研究与核小体中的组蛋白蛋白复合的DNA，核小体是细胞中DNA的基本包装单位。我们将确定NER蛋白如何进入核小体中的DNA损伤，是由损伤的结构和动力学特性决定的，以促进或抑制修复。我们将获得对NER的DNA损伤识别机制的新见解，这可能会导致开发更有效的、对NER不敏感的化疗药物，因为当前药物的疗效会受到NER的损害。此外，这种了解将有助于在许多环境污染物中确定最具遗传毒性的致癌前体，从而能够制定更有针对性的减排政策和相关健康风险的生物监测方法。