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（申请人提供）：人类基因组不断受到环境污染物、人体组织在炎症反应过程中分泌的内源性活性氧化物质以及阳光中的紫外线成分的持续攻击，其中多环芳香族化合物是致癌的外源性环境污染物。有毒废物堆和超级基金场所、空气中的颗粒物以及我们的食物和水中发现的化石燃料燃烧副产品化合物 来自多环芳香族化合物的 DNA 损伤。化合物、与炎症相关的活性氧化物质和紫外线会导致恶性突变的积累，从而导致多种人类癌症。然而，并非所有 DNA 损伤都同样有效地促进人类疾病：尽管损伤可以被人类切除。在核苷酸切除修复（NER）机制中，一些DNA损伤被快速修复，一些被缓慢修复，还有一些对NER完全具有抵抗力，因此具有特别的基因毒性。NER的至关重要性在毁灭性的人类干皮病中得到了证明。然而，当 NER 正常时，为什么某些 DNA 损伤具有 NER 抗性，而其他损伤则不然，目前尚不清楚。通过关注 NER 中损伤识别的关键步骤，我们发现损伤的识别程度取决于损伤对 DNA 施加的不稳定或稳定的程度：稳定导致损伤。我们将剖析一组选定的 DNA 损伤的结构、动态和热力学特性，这些特性决定它们是否被人类 XPC-RAD23B 损伤识别因子的酵母直系同源物 Rad4-Rad23 识别。 1 我们将确定含有损伤的 DNA 的局部热力学稳定性调节其识别的程度。 在目标 2 中，我们将确定 Rad4-Rad23 成功结合的分子机制。识别病变并正确招募后续 NER 因子，以及该途径的结合途径和自由能如何依赖于病变结构。在目标 3 中，我们将研究核小体中 DNA 与组蛋白的复合物，核小体是细胞中 DNA 的基本包装单位。确定 NER 蛋白如何通过损伤的结构和动态特性来控制核小体中的 DNA 损伤，以促进或抑制修复。我们将获得的对 NER DNA 损伤识别机制的新见解可能会导致开发更有效、对 NER 较不敏感的化疗药物，因为现有药物的疗效会受到 NER 的损害。此外，这种了解将有助于在许多环境污染物中识别最具遗传毒性的致癌前体，从而允许开发新的化疗药物。更有针对性的减排政策和相关健康风险的生物监测方法。