Mutational Signatures of a Combined Environmental Exposure: Arsenic and Ultraviolet Radiation

综合环境暴露的突变特征：砷和紫外线辐射

基本信息

批准号：
10330581
负责人：
LAURIE G HUDSON
金额：
$ 50.85万
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：
2020
资助国家：
美国
起止时间：
2020-04-06 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10330581
关键词：
Address Agreement Animal Model Arsenic Arsenites Biochemical Cancer Etiology Carcinogens Cell Culture Techniques Cell model Cells Characteristics Chronic Complex Computer Analysis DNA Damage DNA Repair DNA Repair Gene DNA Sequence Alteration Data Defect Development Environmental Exposure Environmental Risk Factor Epidemiology Exons Exposure to Histopathology Human Induced Mutation Intervention Introns Lead Malignant Neoplasms Malignant neoplasm of lung Metal exposure Metals Molecular Motivation Mus Mutagenesis Mutation Mutation Analysis Mutation Spectra Nucleotide Excision Repair Nucleotide Excision Repair Inhibition Outcome Outcome Study Pattern Persons Positioning Attribute Predictive Value Prevention strategy Process Publishing Research Design Research Personnel Risk Safety Sampling Skin Skin Cancer Skin Carcinogenesis Somatic Mutation Tobacco smoke Transcription-Coupled Repair UV induced UV induced DNA damage Ultraviolet Rays World Health Organization XPA gene Zinc Zinc Fingers Zinc supplementation base cancer epidemiology carcinogenesis carcinogenicity combinatorial drinking water genome sequencing in vivo insight keratinocyte lifestyle factors new technology next generation sequencing predictive modeling repaired research study skin squamous cell carcinoma tool tumor whole genome xeroderma pigmentosum group A complementing protein

项目摘要

Project Summary Over 200 million people worldwide are chronically exposed to arsenic in drinking water at concentrations above the EPA or World Health Organization safety standard. There is strong experimental and epidemiological evidence that low levels of arsenic in combination with other environmental insults such as ultraviolet radiation (UVR) increases carcinogenesis, suggesting arsenic is a co-carcinogen in humans. However, little is known about the molecular mechanisms of arsenic co-carcinogenesis or effective strategies for prevention of arsenic- augmented cancers. Recent advances in analysis of next generation sequencing have given rise to powerful tools to define distinct mutational signatures in tumors that identify specific defects in DNA repair processes or carcinogenic exposures as part of cancer etiology. In current proposed study we will apply this new technology to advance our understanding of arsenic as a co-carcinogen when combined with the DNA damaging UVR. We have published an extensive body of work demonstrating that arsenic interferes with the zinc finger motifs of select DNA repair proteins leading to decreased repair capacity and increased DNA damage and mutations that are alleviated by zinc. A preliminary mutation pattern analysis of normal human keratinocytes exposed to 0.1 µM arsenite, UVR, or both revealed that this low concentration of arsenite was sufficient to enhance UVR- induced C>T mutations and zinc supplement reduced C>T mutations suggesting a potential intervention. Furthermore, the mutational signatures generated by UVR and arsenite differ from those of UVR alone, indicating that arsenite modifies the mutation spectrum rather than simply amplify the UVR signature. Based on our published and preliminary findings, we hypothesize that arsenic enhances UVR-induced skin carcinogenesis by disrupting the zinc finger function of the key DNA repair protein XPA, which in turn, results in deficient nucleotide excision repair leading to greater accumulation of somatic mutations. In Aim 1, we will determine whether exposure to arsenic, UVR or both generates unique mutational signatures and the impact of zinc on identified signatures using whole genome sequencing and advanced computational approaches developed by co-investigator Dr. Alexandrov. Aim 2 will investigate the molecular mechanism of C>T mutation enhancement by arsenic through transcription-coupled nucleotide excision repair inhibition using both biochemical approaches and computational analysis of whole genome sequencing data. In Aim 3, we will use a proven animal model of UVR-induced skin carcinogenesis to define in vivo mutational signatures from UVR- induced tumors with or without arsenic and the impact of zinc on the mutation signature. The outcomes from our rigorously designed studies are expected to provide the first experimental definition of a metal-induced mutation signature and the first analysis of mutational signatures generated by combination exposures to two important and relevant environmental insults, as well as the insights into mechanisms by which arsenic enhances UVR-induced carcinogenesis and how zinc confers protection.

项目摘要全球超过2亿人在饮用水中长期以上暴露于砷的浓度上 EPA或世界卫生组织的安全标准。有强大的实验和流行病学证据表明，低水平的砷与其他环境伤害（例如紫外线辐射）结合（UVR）增加了致癌作用，这表明砷是人类的共霉菌原。但是，鲜为人知关于砷共癌的分子机制或预防砷的有效策略增强癌症。下一代测序分析的最新进展已引起强大的在肿瘤中定义不同突变特征的工具，这些突变特征在DNA修复过程中识别特定缺陷或致癌性暴露是癌症病因的一部分。在当前建议的研究中，我们将应用这项新技术当我们与DNA损害UVR结合使用时，我们将对砷作为共霉菌素的理解。我们已经发表了广泛的工作，证明了砷对锌指图案的干扰选择DNA修复蛋白，从而提高维修能力并增加DNA损伤和突变锌减轻了。正常人角质形成细胞的初步突变模式分析暴露于 0.1 µm砷，UVR或两者都表明，这种低浓度的砷足以增强UVR- 诱导的C> T突变和锌补充减少了C> T突变，表明潜在的干预。此外，UVR和砷产生的突变特征与单独的UVR不同，表明砷会修饰突变谱，而不是简单地放大UVR特征。基于我们发表的初步发现，我们假设砷增强了UVR诱导的皮肤通过破坏关键DNA修复蛋白XPA的锌指功能来发生致癌作用，这又导致缺乏核丁基惊喜修复，导致体细胞突变的积累。在AIM 1中，我们将确定暴露于砷，UVR或两者是否会产生独特的突变特征以及使用整个基因组测序和高级计算方法识别出的标志的锌由共同投资者Alexandrov博士开发。 AIM 2将研究C> T突变的分子机制通过转录耦合的核苷酸惊喜修复抑制砷的增强整个基因组测序数据的生化方法和计算分析。在AIM 3中，我们将使用 UVR诱导的皮肤致癌作用的可靠动物模型，从UVR-定义体内突变特征诱导有或没有砷的肿瘤以及锌对突变特征的影响。结果我们严格设计的研究有望提供金属诱导的第一个实验定义突变签名和首次分析由两种结合暴露产生的突变特征重要和相关的环境侮辱以及对砷的机制的见解增强UVR诱导的致癌作用以及锌的贡献如何保护。