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

Xiaoxin S. Xu, Latha Narayanan, Brady Dunklee, R. Michael Liskay, Peter M. Glazer

Research output: Contribution to journalArticle

25 Scopus citations

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 λ shuttle vector for mutation detection. In Pms2 nullizygous animals, the mutation frequency in the supFG1 reporter gene was increased from 210 × 10-5 in untreated animals to 734 × 10-5 after 6 Gy of IR (an increase of 524 mutants per 105), whereas the frequency in wild-type mice increased from 1.9 × 10-5 to 10.2 × 10-5 (an increase of only 8.3 mutants per 105). Similarly, when the λ cII gene was used as a reporter, the mutation frequency in nullizygous mice was increased from 16.3 × 10-5 to 42.3 × 10-5 after IR (an increase of 26.0 × 10-5), whereas the frequency in wild-type mice increased from 2.4 × 10-5 to 9.4 × 10-5 (an increase of only 7.0 × 10-5). The pattern of IR-induced mutations in the MMR-deficient animals was notable for single bp deletions and insertions in mononucleotide repeat sequences, along with a slight increase in transversions. Overall, these results suggest that MMR-deficiency confers hypermutability to IR, and that much of this hypermutability can be attributed to induced instability of simple sequence repeats. Hence, MMR influences not only the survival but also the mutability of cells in response to IR.

Original languageEnglish (US)
Pages (from-to)3775-3780
Number of pages6
JournalCancer Research
Volume61
Issue number9
StatePublished - May 1 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Xu, X. S., Narayanan, L., Dunklee, B., Liskay, R. M., & Glazer, P. M. (2001). Hypermutability to ionizing radiation in mismatch repair-deficient, Pms2 knockout mice. Cancer Research, 61(9), 3775-3780.