Nickel and toxic topoisomerase I products

镍和有毒拓扑异构酶 I 产品

• 批准号: 10208065
• 负责人: Anatoly Zhitkovich
• 金额: $ 35.74万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10208065
• 关键词: Affect; Alloys; Aneuploidy; Animals; BRCA1 gene; Biochemical; Biological Assay; Cancerous; Carcinogens; Cell Survival; Cells; Chemicals; Chromosomal Rearrangement; Chromosome abnormality; Chromosomes; Complex; Cultured Cells; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Sequence Alteration; DNA replication fork; DNA-protein crosslink; Defect; Dependence; Dose; Double Strand Break Repair; Environment; Environmental Pollution; Enzymes; Event; Exposure to; Fiber; Fossil Fuels; Genetic; Genetic Recombination; Genomics; Human; Incineration; Individual; Industrialization; Inhalation; Ions; Ligation; Link; Lung; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Metals; Methodology; Microtubules; Mitotic spindle; Modeling; Molecular; Molecular Abnormality; Mutation; Nickel; Nonhomologous DNA End Joining; Nose; Occupational Exposure; Oncogenic; Population; Process; Production; Risk Assessment; Role; Rotation; S Phase; Source; Stainless Steel; Superhelical DNA; Testing; Time; Tumorigenicity; Type I DNA Topoisomerases; Work; animal tissue; base; cancer risk; carcinogenicity; cell transformation; cost; design; dietary; exposed human population; genotoxicity; homologous recombination; improved; lung development; novel; novel marker; nuclease; pollutant; prevent; recombinational repair; repaired; single molecule; superfund site; wasting

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.

项目摘要 镍（Ni）是一种主要的工业金属，也是一种常见的环境污染物， 被确定为人类致癌物。镍化合物在职业接触人群中的吸入 已被发现会导致肺癌和鼻癌。不同形式的镍的致瘤性与 Ni（II）离子的细胞内存在。镍的致癌活性机制知之甚少， 因为镍化合物在标准致突变性试验中为弱或阴性，而镍（II）离子不 与DNA反应。因此，镍通常被描述为非遗传毒性致癌物。然而，尼- 处理培养细胞和淋巴细胞从镍暴露工人一直显示存在 通常起源于DNA双链断裂（DSB）的染色体重排。也 与其非遗传毒性描述相矛盾的是，Ni（II）能够引起共价DNA-蛋白质交联 （DPC）在实验动物和职业暴露的个人。的存在 染色体异常和DPC，尽管明显缺乏致突变性和DNA反应性 表明Ni可能涉及一些不寻常的遗传毒性机制。根据广泛的初步 结果，该项目旨在研究一种新的假设，即Ni（II）引起DSB，DPC， 通过诱导遗传毒性拓扑异构酶I-DNA产物进行细胞转化。拟议的研究将 确定（1）在DSB的同源重组修复中Ni（II）诱导缺陷的机制，（2） 易错DSB修复在Ni（II）致癌基因变化产生中的重要性，以及 (3)镍诱导的含拓扑异构酶I的DPC的形成及其病理生理意义， DNA断裂。这一工作的完成有望揭示该疾病的分子机制。 一种非诱变致癌物Ni引起的致癌遗传异常的形成及新的鉴定 DNA损伤的生物标志物。