Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance

Shannon L. Gibson, Latha Narayanan, Denise Campisi Hegan, Andrew B. Buermeyer, R. Michael Liskay, Peter M. Glazer

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Inherited defects in genes associated with DNA mismatch repair (MMR) have been linked to familial colorectal cancer. Cells deficient in MMR are genetically unstable and demonstrate a tolerance phenotype in response to certain classes of DNA damage. Some sporadic human cancers also show abnormalities in MMR gene function, typically due to diminished expression of one of the MutL homologs, MLH1. Here, we report that overexpression of the MutL homolog, human PMS2, can also cause a disruption of the MMR pathway in mammalian cells, resulting in hypermutability and DNA damage tolerance. A mouse fibroblast cell line carrying a recoverable lambda phage shuttle vector for mutation detection was transfected with either a vector designed to express hPMS2 or with an empty vector control. Cells overexpressing hPMS2 were found to have elevated spontaneous mutation frequencies at the cII reporter gene locus. They also showed an increase in the level of mutations induced by the alkylating agent, methynitrosourea (MNU). Clonogenic survival assays demonstrated increased survival of the PMS2-overexpressing cells following exposure to MNU, consistent with the induction of a damage tolerance phenotype. Similar results were seen in cells expressing a mutant PMS2 gene, containing a premature stop codon at position 134 and representing a variant found in an individual with familial colon cancer. These results show that dysregulation of PMS2 gene expression can disrupt MMR function in mammalian cells and establish an additional carcinogenic mechanism by which cells can develop genetic instability and acquire resistance to cytotoxic cancer therapies.

Original languageEnglish (US)
Pages (from-to)195-202
Number of pages8
JournalCancer Letters
Volume244
Issue number2
DOIs
StatePublished - Dec 8 2006

Keywords

  • Alkylating agent
  • Lambda shuttle vector
  • Methylnitrosourea
  • Mismatch repair (MMR)
  • PMS2
  • cII

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Gibson, S. L., Narayanan, L., Hegan, D. C., Buermeyer, A. B., Liskay, R. M., & Glazer, P. M. (2006). Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance. Cancer Letters, 244(2), 195-202. https://doi.org/10.1016/j.canlet.2005.12.009