ROLE OF DNA MISMATCH REPAIR IN THE CYTOTOXICITY OF IONIZING-RADIATION

The DNA mismatch repair (MMR) system in mammalian cells not only serve s to correct base mispairs and other replication errors, but it also i nfluences the cellular response to certain forms of DNA damage. Cells that are deficient in MMR are relatively resistant to alkylation damag e because, in wild-type cells, the MMR system is thought to promote to xicity via futile repair of alkylated mispairs. Conversely, MMR-defici ent cells are sensitive to UV light, possibly due to the requirement f or MMR factors in transcription-coupled repair of active genes. MMR de ficiency has been associated with familial and sporadic carcinomas of the colon and other sites, and so, we sought to determine the influenc e of MMR status on cellular response to ionizing radiation, an agent c ommonly used for cancer therapy. Fibroblast cell lines were establishe d from transgenic mice carrying targeted disruptions of one of three M MR genes in mammalian cells: Pms2, Mlh1, or Msh2. In comparison to wil d-type cell lines from related mice, the Pms2-, Mlh1-, or Msh2-nullizy gous cell lines were found to exhibit higher levels of clonogenic surv ival following exposure to ionizing radiation. Because ionizing radiat ion generates a variety of lesions in DNA., the differences in surviva l 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.