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：
10844717
负责人：
LAURIE G HUDSON
金额：
$ 50.33万
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/10844717
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 Environment Environmental Exposure Environmental Risk Factor Epidemiology Exons Exposure to Histopathology Human Induced Mutation Intervention Introns 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 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 cancer epidemiology carcinogenesis carcinogenicity combinatorial drinking water genome sequencing in vivo insight keratinocyte lifestyle factors meter new technology next generation sequencing predictive modeling repaired 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.

项目概要全球有超过 2 亿人长期接触饮用水中砷浓度高于 EPA或世界卫生组织的安全标准有很强的实验性和流行病学性。有证据表明砷含量低与紫外线辐射等其他环境损害相结合（紫外线）会增加致癌作用，表明砷是人类的共同致癌物，但人们对此知之甚少。砷协同致癌的分子机制或预防砷的有效策略下一代测序分析的最新进展带来了强大的癌症。定义肿瘤中不同突变特征的工具，识别 DNA 修复过程中的特定缺陷或致癌暴露作为癌症病因学的一部分，在当前拟议的研究中，我们将应用这项新技术。加深我们对砷与 DNA 损伤性 UVR 结合时作为共致癌物的认识。发表了大量的工作，证明砷会干扰锌指基序选择导致修复能力下降、DNA 损伤和突变增加的 DNA 修复蛋白对暴露于锌的正常人角质形成细胞的初步突变模式分析。 0.1 µM 亚砷酸盐、UVR 或两者均表明，这种低浓度的亚砷酸盐足以增强 UVR- 诱导的 C>T 突变和锌补充剂减少的 C>T 突变表明潜在的干预措施。此外，UVR 和亚砷酸盐产生的突变特征与单独 UVR 产生的突变特征不同，表明亚砷酸盐改变了突变谱，而不是简单地放大了 UVR 特征。我们已发表的初步研究结果表明，砷会增强紫外线引起的皮肤通过破坏关键 DNA 修复蛋白 XPA 的锌指功能来致癌，进而导致在目标 1 中，核苷酸切除修复缺陷会导致更多的体细胞突变积累。确定暴露于砷、紫外线或两者是否会产生独特的突变特征以及其影响使用全基因组测序和先进计算方法识别特征的锌由共同研究员 Alexandrov 博士开发的 Aim 2 将研究 C>T 突变的分子机制。砷通过转录偶联核苷酸切除修复抑制作用增强在目标 3 中，我们将使用全基因组测序数据的生化方法和计算分析。经证实的 UVR 诱导皮肤癌动物模型，用于定义 UVR 的体内突变特征有或没有砷诱发的肿瘤以及锌对突变特征的影响。我们严格设计的研究预计将提供金属诱导的第一个实验定义突变特征以及对两种组合暴露产生的突变特征的首次分析重要且相关的环境损害，以及对砷影响机制的见解增强紫外线诱导的致癌作用以及锌如何提供保护。