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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：
Anatoly Zhitkovich
金额：
$ 35.74万
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/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

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