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：
10542727
负责人：
Anatoly Zhitkovich
金额：
$ 35.89万
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/10542727
关键词：
Affect Alloys Aneuploidy Animal Experiments 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 Pollutants Environmental Pollution Enzymes Event Exposure to Fiber Fossil Fuels Genetic Genetic Induction 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 Repression Risk Assessment Role Rotation S phase Source Stainless Steel Superhelical DNA Testing Time Tumorigenicity Type I DNA Topoisomerases Work animal tissue cancer risk carcinogenicity cell transformation cost design dietary exposed human population genotoxicity homologous recombination improved lung development manufacture 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.

项目摘要镍（NI）是一种主要的工业金属，是一种牢固的环境污染物建立为人类致癌。在职业暴露人群中吸入NI化合物已发现引起肺癌和鼻癌。不同形式的Ni的肿瘤性与 Ni（II）离子的细胞内存在。 Ni的致癌活性机制知之甚少，由于NI化合物在标准诱变分析中是弱或负的，而Ni（II）离子不得与DNA反应。因此，Ni通常被描述为非核癌。但是，来自NI-PAPERS工人的经过处理的培养细胞和淋巴细胞始终显示出存在染色体重排通常来自DNA双链断裂（DSB）。还与其非核描述相矛盾的是Ni（II）引起共价DNA蛋白交联的能力（DPC）在实验动物和职业暴露的个体中。存在染色体异常和DPC，尽管显然缺乏诱变性和DNA反应性表明NI可能具有一些异常的遗传毒性机制。基于广泛的初步结果，该项目旨在研究一个新的假设，即Ni（II）导致DSB，DPC和通过诱导遗传毒性拓扑异构酶I-DNA产物诱导细胞转化。拟议的研究将确定（1）Ni（ii）诱导的DSB同源重组修复中缺陷的机制，（2）容易出错的DSB修复在Ni（ii）的致癌遗传变化中的重要性，（3）NI诱导的拓扑异构酶I含DPC的形成和病理生理意义和 DNA断裂。这项工作的完成有望发现非毒理致癌物Ni形成致癌遗传异常并鉴定新型 DNA损伤的生物标志物被这种金属损伤。