Role of DNA mismatch repair in the cytotoxicity of ionizing radiation

James A. Fritzell, Latha Narayanan, Sean M. Baker, C. Eric Bronner, Susan E. Andrew, Tomas A. Prolla, Allan Bradley, Frank R. Jirik, R. Michael Liskay, Peter M. Glazer

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77 Scopus citations

Abstract

The DNA mismatch repair (MMR) system in mammalian cells not only serves to correct base mispairs and other replication errors, but it also influences the cellular response to certain forms of DNA damage. Cells that are deficient in MMR are relatively resistant to alkylation damage because, in wild-type cells, the MMR system is thought to promote toxicity via futile repair of alkylated mispairs. Conversely, MMR-deficient cells are sensitive to UV light, possibly due to the requirement for MMR factors in transcription-coupled repair of active genes. MMR deficiency has been associated with familial and sporadic carcinomas of the colon and other sites, and so, we sought to determine the influence of MMR status on cellular response to ionizing radiation, an agent commonly used for cancer therapy. Fibroblast cell lines were established from transgenic mice carrying targeted disruptions of one of three MMR genes in mammalian cells: Pms2, Mlh1, or Msh2. In comparison to wild-type cell lines from related mice, the Pms2-, Mlh1-, or Msh2-nullizygous cell lines were found to exhibit higher levels of clonogenic survival following exposure to ionizing radiation. Because ionizing radiation generates a variety of lesions in DNA, the differences in survival may reflect a role for MMR in processing a subset of these lesions, such as damaged bases. These results both identify a new class of DNA- damaging agents whose effects are modulated by the MMR system and may help to elucidate pathways of radiation response in cancer cells.

Original languageEnglish (US)
Pages (from-to)5143-5147
Number of pages5
JournalCancer Research
Volume57
Issue number22
StatePublished - Nov 15 1997

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Fritzell, J. A., Narayanan, L., Baker, S. M., Bronner, C. E., Andrew, S. E., Prolla, T. A., Bradley, A., Jirik, F. R., Liskay, R. M., & Glazer, P. M. (1997). Role of DNA mismatch repair in the cytotoxicity of ionizing radiation. Cancer Research, 57(22), 5143-5147.