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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells.

Authors: Scanlon, Susan E; Scanlon, Christine D; Hegan, Denise C; Sulkowski, Parker L; Glazer, Peter M

Published In Carcinogenesis, (2017 06 01)

Abstract: The heavy metal nickel is a known carcinogen, and occupational exposure to nickel compounds has been implicated in human lung and nasal cancers. Unlike many other environmental carcinogens, however, nickel does not directly induce DNA mutagenesis, and the mechanism of nickel-related carcinogenesis remains incompletely understood. Cellular nickel exposure leads to signaling pathway activation, transcriptional changes and epigenetic remodeling, processes also impacted by hypoxia, which itself promotes tumor growth without causing direct DNA damage. One of the mechanisms by which hypoxia contributes to tumor growth is the generation of genomic instability via down-regulation of high-fidelity DNA repair pathways. Here, we find that nickel exposure similarly leads to down-regulation of DNA repair proteins involved in homology-dependent DNA double-strand break repair (HDR) and mismatch repair (MMR) in tumorigenic and non-tumorigenic human lung cells. Functionally, nickel induces a defect in HDR capacity, as determined by plasmid-based host cell reactivation assays, persistence of ionizing radiation-induced DNA double-strand breaks and cellular hypersensitivity to ionizing radiation. Mechanistically, we find that nickel, in contrast to the metalloid arsenic, acutely induces transcriptional repression of HDR and MMR genes as part of a global transcriptional pattern similar to that seen with hypoxia. Finally, we find that exposure to low-dose nickel reduces the activity of the MLH1 promoter, but only arsenic leads to long-term MLH1 promoter silencing. Together, our data elucidate novel mechanisms of heavy metal carcinogenesis and contribute to our understanding of the influence of the microenvironment on the regulation of DNA repair pathways.

PubMed ID: 28472268 Exiting the NIEHS site

MeSH Terms: Arsenites/toxicity; Cell Hypoxia/genetics; Cell Line, Tumor; Cell Transformation, Neoplastic/chemically induced; Cell Transformation, Neoplastic/genetics; DNA Breaks, Double-Stranded/drug effects; DNA Breaks, Double-Stranded/radiation effects; DNA Repair Enzymes*; DNA Repair/drug effects*; DNA Repair/radiation effects; Down-Regulation; Genomic Instability; Humans; Lung Neoplasms/genetics*; Lung Neoplasms/pathology; Lung/metabolism*; Lung/pathology; Nickel/toxicity*; Teratogens/toxicity; Trace Elements/toxicity*

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