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:
- 金额:$ 50.85万
- 依托单位:
- 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:
- 关键词:AddressAgreementAnimal ModelArsenicArsenitesBiochemicalCancer EtiologyCarcinogensCell Culture TechniquesCell modelCellsCharacteristicsChronicComplexComputer AnalysisDNA DamageDNA RepairDNA Repair GeneDNA Sequence AlterationDataDefectDevelopmentEnvironmental ExposureEnvironmental Risk FactorEpidemiologyExonsExposure toHistopathologyHumanInduced MutationInterventionIntronsLeadMalignant NeoplasmsMalignant neoplasm of lungMetal exposureMetalsMolecularMotivationMusMutagenesisMutationMutation AnalysisMutation SpectraNucleotide Excision RepairNucleotide Excision Repair InhibitionOutcomeOutcome StudyPatternPersonsPositioning AttributePredictive ValuePrevention strategyProcessPublishingResearch DesignResearch PersonnelRiskSafetySamplingSkinSkin CancerSkin CarcinogenesisSomatic MutationTobacco smokeTranscription-Coupled RepairUV inducedUV induced DNA damageUltraviolet RaysWorld Health OrganizationXPA geneZincZinc FingersZinc supplementationbasecancer epidemiologycarcinogenesiscarcinogenicitycombinatorialdrinking watergenome sequencingin vivoinsightkeratinocytelifestyle factorsnew technologynext generation sequencingpredictive modelingrepairedresearch studyskin squamous cell carcinomatooltumorwhole genomexeroderma 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.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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
Illuminating the functions and translational potential of CDC42BP/MRCK kinases in ovarian cancer
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- 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
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10707512 - 财政年份:2017
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$ 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
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10353202 - 财政年份:2017
- 资助金额:
$ 50.85万 - 项目类别:
Zinc Chemoprevention of Arsenic Co-Carcinogenesis
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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
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8625502 - 财政年份:2012
- 资助金额:
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