Hypermutability to ionizing radiation in mismatch repair-deficient, Pms2 knockout mice

DNA mismatch repair (MMR) has been shown to play a role in the cytotoxicity of ionizing radiation (IR), as cell lines established from MMR-deficient m ice exhibit higher clonogenic survival after IR than do cell lines from wil d-type littermates. To test whether this tolerance phenotype would render M MR-deficient animals hypermutable to IR, we compared In mutagenesis of Pms2 -deficient versus wild-type transgenic mice carrying a lambda shuttle vecto r for mutation detection. In Pms2 nullizygous animals, the mutation frequen cy in the supFG1 reporter gene was increased from 210 x 10(-5) in untreated animals to 734 x 10(-5) after 6 Gy of IR (an increase of 524 mutants per 1 0(5)), whereas the frequency in wild-type mice increased from 1.9 x 10(-5) to 10.2 x 10(-5) (an increase of only 8.3 mutants per 10(5)), Similarly, wh en the lambda cII gene was used as a reporter, the mutation frequency In nu llizygous mire was increased from 16.3 x 10(-5) to 42.3 x 10(-5) after IR ( an increase of 26.0 x 10(-5)), whereas the frequency in wild-type mice Incr eased from 2.4 x 10(-5) to 9.4 x 10(-5) (an increase of only 7.0 x 10(-5)). The pattern of IR-induced mutations in the MMR-deficient animals was notab le for single bp deletions and insertions in mononucleotide repeat sequence s, along with a slight increase in transversions. Overall, those results su ggest that MMR-deficiency confers hypermutability to IR, and that much of t his hypermutability can be attributed to induced instability of simple sequ ence repents. Hence, MMR influences not only the survival but also the muta bility of cells in response to IR.