Nickel and toxic topoisomerase I products
镍和有毒拓扑异构酶 I 产品
基本信息
- 批准号:10208065
- 负责人:
- 金额:$ 35.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-18 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAlloysAneuploidyAnimalsBRCA1 geneBiochemicalBiological AssayCancerousCarcinogensCell SurvivalCellsChemicalsChromosomal RearrangementChromosome abnormalityChromosomesComplexCultured CellsDNADNA DamageDNA Double Strand BreakDNA RepairDNA Sequence AlterationDNA replication forkDNA-protein crosslinkDefectDependenceDoseDouble Strand Break RepairEnvironmentEnvironmental PollutionEnzymesEventExposure toFiberFossil FuelsGeneticGenetic RecombinationGenomicsHumanIncinerationIndividualIndustrializationInhalationIonsLigationLinkLungLymphocyteMalignant NeoplasmsMalignant neoplasm of lungMeasurementMetalsMethodologyMicrotubulesMitotic spindleModelingMolecularMolecular AbnormalityMutationNickelNonhomologous DNA End JoiningNoseOccupational ExposureOncogenicPopulationProcessProductionRisk AssessmentRoleRotationS PhaseSourceStainless SteelSuperhelical DNATestingTimeTumorigenicityType I DNA TopoisomerasesWorkanimal tissuebasecancer riskcarcinogenicitycell transformationcostdesigndietaryexposed human populationgenotoxicityhomologous recombinationimprovedlung developmentnovelnovel markernucleasepollutantpreventrecombinational repairrepairedsingle moleculesuperfund sitewasting
项目摘要
Project Summary
Nickel (Ni) is a major industrial metal and a common environmental contaminant that is firmly
established as a human carcinogen. Inhalation of Ni compounds in occupationally exposed populations
has been found to cause lung and nasal cancers. Tumorigenicity of different forms of Ni was linked to
the intracellular presence of Ni(II) ions. Mechanisms of carcinogenic activity of Ni are poorly understood,
as Ni compounds were weak or negative in the standard mutagenicity assays and Ni(II) ions do not
react with DNA. Consequently, Ni is commonly described as a nongenotoxic carcinogen. However, Ni-
treated cultured cells and lymphocytes from Ni-exposed workers have consistently shown the presence
of chromosomal rearrangements that typically originate from DNA double-strand breaks (DSBs). Also
contradicting its nongenotoxic description is the ability of Ni(II) to cause covalent DNA-protein crosslinks
(DPCs) in experimental animals and in occupationally exposed individuals. The presence of
chromosomal abnormalities and DPCs despite the apparent lack of mutagenicity and DNA reactivity
suggests that Ni may engage some unusual genotoxicity mechanisms. Based on extensive preliminary
results, this project is designed to investigate a novel hypothesis that Ni(II) causes DSBs, DPCs, and
cell transformation by inducing genotoxic topoisomerase I-DNA products. The proposed studies will
determine (1) mechanisms of Ni(II)-induced defects in homologous recombination repair of DSBs, (2)
the importance of error-prone DSB repair in the production of oncogenic genetic changes by Ni(II), and
(3) formation and pathophysiological significance of Ni-induced topoisomerase I-containing DPCs and
DNA breaks. The completion of this work is expected to uncover molecular mechanisms of the
formation of oncogenic genetic abnormalities by a nonmutagenic carcinogen Ni and identify novel
biomarkers of DNA damage by this metal.
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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Anatoly Zhitkovich其他文献
Anatoly Zhitkovich的其他文献
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{{ truncateString('Anatoly Zhitkovich', 18)}}的其他基金
Indirect Genotoxicity in Metal Carcinogenesis
金属致癌过程中的间接遗传毒性
- 批准号:
10527323 - 财政年份:2020
- 资助金额:
$ 35.74万 - 项目类别:
Indirect Genotoxicity in Metal Carcinogenesis
金属致癌过程中的间接遗传毒性
- 批准号:
10304906 - 财政年份:2020
- 资助金额:
$ 35.74万 - 项目类别:
Regulation of p53 and Checkpoint Signaling by Chromium(VI)
Chromium(VI) 对 p53 和检查点信号传导的调节
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10306386 - 财政年份:2017
- 资助金额:
$ 35.74万 - 项目类别:
Regulation of p53 and Checkpoint Signaling by Chromium(VI)
Chromium(VI) 对 p53 和检查点信号传导的调节
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10057383 - 财政年份:2017
- 资助金额:
$ 35.74万 - 项目类别:
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