Arsenic Inhibits DNA Mismatch Repair by Promoting EGFR Expression and PCNA Phosphorylation |
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Authors: | Dan Tong Janice Ortega Christine Kim Jian Huang Liya Gu Guo-Min Li |
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Affiliation: | From the ‡College of Life Sciences, Wuhan University, Wuhan, China 430072.;§Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536, and ;¶Tsinghua University School of Medicine, Beijing, China 100084 |
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Abstract: | Both genotoxic and non-genotoxic chemicals can act as carcinogens. However, while genotoxic compounds lead directly to mutations that promote unregulated cell growth, the mechanism by which non-genotoxic carcinogens lead to cellular transformation is poorly understood. Using a model non-genotoxic carcinogen, arsenic, we show here that exposure to arsenic inhibits mismatch repair (MMR) in human cells, possibly through its ability to stimulate epidermal growth factor receptor (EGFR)-dependent tyrosine phosphorylation of proliferating cellular nuclear antigen (PCNA). HeLa cells exposed to exogenous arsenic demonstrate a dose- and time-dependent increase in the levels of EGFR and tyrosine 211-phosphorylated PCNA. Cell extracts derived from arsenic-treated HeLa cells are defective in MMR, and unphosphorylated recombinant PCNA restores normal MMR activity to these extracts. These results suggest a model in which arsenic induces expression of EGFR, which in turn phosphorylates PCNA, and phosphorylated PCNA then inhibits MMR, leading to increased susceptibility to carcinogenesis. This study suggests a putative novel mechanism of action for arsenic and other non-genotoxic carcinogens. |
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Keywords: | DNA mismatch repair DNA repair epidermal growth factor receptor (EGFR) nucleic acid proliferating cell nuclear antigen (PCNA) |
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