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

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.
项目总结

项目成果

期刊论文数量(0)
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LAURIE G HUDSON其他文献

LAURIE G HUDSON的其他文献

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{{ truncateString('LAURIE G HUDSON', 18)}}的其他基金

Pilot Project Core
试点项目核心
  • 批准号:
    10393303
  • 财政年份:
    2022
  • 资助金额:
    $ 50.85万
  • 项目类别:
Pilot Project Core
试点项目核心
  • 批准号:
    10689705
  • 财政年份:
    2022
  • 资助金额:
    $ 50.85万
  • 项目类别:
Illuminating the functions and translational potential of CDC42BP/MRCK kinases in ovarian cancer
阐明 CDC42BP/MRCK 激酶在卵巢癌中的功能和翻译潜力
  • 批准号:
    10216717
  • 财政年份:
    2021
  • 资助金额:
    $ 50.85万
  • 项目类别:
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
  • 批准号:
    10844717
  • 财政年份:
    2020
  • 资助金额:
    $ 50.85万
  • 项目类别:
Biomarkers and mechanisms of metal and mixed metal exposures
金属和混合金属暴露的生物标志物和机制
  • 批准号:
    10707512
  • 财政年份:
    2017
  • 资助金额:
    $ 50.85万
  • 项目类别:
Biomarkers and mechanisms of metal and mixed metal exposures
金属和混合金属暴露的生物标志物和机制
  • 批准号:
    10353202
  • 财政年份:
    2017
  • 资助金额:
    $ 50.85万
  • 项目类别:
Zinc Chemoprevention of Arsenic Co-Carcinogenesis
锌对砷协同致癌作用的化学预防
  • 批准号:
    8762020
  • 财政年份:
    2014
  • 资助金额:
    $ 50.85万
  • 项目类别:
Zinc Chemoprevention of Arsenic Co-Carcinogenesis
锌对砷协同致癌作用的化学预防
  • 批准号:
    9325454
  • 财政年份:
    2014
  • 资助金额:
    $ 50.85万
  • 项目类别:
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
  • 财政年份:
    2012
  • 资助金额:
    $ 50.85万
  • 项目类别:
Capitalizing on NSAID enantiomer selectivity for cancer prevention and therapy(PQ
利用 NSAID 对映体选择性进行癌症预防和治疗 (PQ
  • 批准号:
    8625502
  • 财政年份:
    2012
  • 资助金额:
    $ 50.85万
  • 项目类别:

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  • 财政年份:
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  • 资助金额:
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  • 项目类别:
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