Arsenic inhibits DNA mismatch repair by promoting EGFR expression and PCNA phosphorylation

Dan Tong, Janice Ortega, Christine Kim, Jian Huang, Liya Gu, Guo Min Li

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 abilitytostimulate 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.

Original languageEnglish (US)
Pages (from-to)14536-14541
Number of pages6
JournalJournal of Biological Chemistry
Volume290
Issue number23
DOIs
StatePublished - Jun 5 2015

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Nuclear Antigens
Phosphorylation
DNA Mismatch Repair
Arsenic
Epidermal Growth Factor Receptor
Repair
Carcinogens
DNA
HeLa Cells
Tyrosine
Lead compounds
Cell growth
Cell Extracts
Carcinogenesis
Cells
Mutation
Growth

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Arsenic inhibits DNA mismatch repair by promoting EGFR expression and PCNA phosphorylation. / Tong, Dan; Ortega, Janice; Kim, Christine; Huang, Jian; Gu, Liya; Li, Guo Min.

In: Journal of Biological Chemistry, Vol. 290, No. 23, 05.06.2015, p. 14536-14541.

Research output: Contribution to journalArticle

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