Arsenic Inhibits DNA Mismatch Repair by Promoting EGFR Expression and PCNA Phosphorylation

This is the authors' abstract. We don't add key points for this paper.

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. Background: Exposure to arsenic is linked to increased risk of human cancer. Results: Arsenic-treated cells have higher levels of EGFR and tyrosine-phosphorylated PCNA and reduced mismatch repair activity. Conclusion: The carcinogenic effect of arsenic may be mediated by its ability to promote EGFR-dependent PCNA phosphorylation, thereby inhibiting mismatch repair. Significance: Arsenic-stimulated posttranslational modification of PCNA represents a novel mechanism of action for non-genotoxic carcinogens.