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：
10374135
负责人：
Anatoly Zhitkovich
金额：
$ 35.85万
依托单位：
BROWN UNIVERSITY
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：
https://reporter.nih.gov/project-details/10374135
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

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.

项目概要镍 (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。职业暴露人群吸入镍化合物已被发现可导致肺癌和鼻癌。不同形式镍的致瘤性与细胞内存在 Ni(II) 离子。对镍的致癌活性机制知之甚少，因为 Ni 化合物在标准致突变性测定中呈弱或阴性，而 Ni(II) 离子则不会与DNA发生反应。因此，镍通常被描述为一种非基因毒性致癌物。然而，镍- 经过处理的培养细胞和来自接触镍的工人的淋巴细胞始终显示出存在通常源自 DNA 双链断裂 (DSB) 的染色体重排。还与其非基因毒性描述相矛盾的是 Ni(II) 引起共价 DNA-蛋白质交联的能力（DPC）在实验动物和职业暴露个体中。的存在尽管明显缺乏致突变性和 DNA 反应性，但染色体异常和 DPC 表明 Ni 可能参与一些不寻常的遗传毒性机制。基于广泛的初步结果，该项目旨在研究 Ni(II) 导致 DSB、DPC 和通过诱导基因毒性拓扑异构酶 I-DNA 产物进行细胞转化。拟议的研究将确定 (1) Ni(II) 诱导 DSB 同源重组修复缺陷的机制，(2) 容易出错的 DSB 修复在 Ni(II) 产生致癌基因变化中的重要性，以及 (3) Ni诱导的含拓扑异构酶I的DPCs的形成及其病理生理学意义 DNA 断裂。这项工作的完成预计将揭示该疾病的分子机制。非诱变致癌物 Ni 形成致癌基因异常并鉴定新的这种金属造成的 DNA 损伤的生物标志物。