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

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 alkylatlon damage because, in wild-type cells, the MMR system is thought to promote toxicity @fia futile repair of alkylated mispairs. Conversely, MMR-deficlent cells are sensitive to UV light, possibly due to the requirement for MMR factors In transcription-coupled repair of active gene& 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 transgenlc mice car rying targeted disruptions of one of three MMR genes in mammalian cells: Pms2, Mihi, or Msh2. In comparison to wild-type cell lines from related mice, the Pms2-, Mihi-, or Msh2-nuilizygous cell lines were found to exhibit higher levels of clonogenic survival following exposure to ion izing radiation. Because ionizing radiation generates a variety oflesions 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.