PMID: 11325851Apr 28, 2001Paper

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

Cancer Research
X S XuP M Glazer

Abstract

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 mice exhibit higher clonogenic survival after IR than do cell lines from wild-type littermates. To test whether this tolerance phenotype would render MMR-deficient animals hypermutable to IR, we compared IR mutagenesis of Pms2-deficient versus wild-type transgenic mice carrying a lambda shuttle vector for mutation detection. In Pms2 nullizygous animals, the mutation frequency 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 10(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, when the lambda cII gene was used as a reporter, the mutation frequency in nullizygous mice 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 increased 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 notable for single bp deletions and insertions in mo...Continue Reading

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