Mutagenesis vol. 18 no. 4 pp. 365-370,
July 2003
© 2003 UK Environmental Mutagen Society/Oxford University Press
Pms2 deficiency results in increased mutation in the Hprt gene but not the Tk gene of Tk+/– transgenic mice
Division of Genetic and Reproductive Toxicology, HFT-120, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, USA
The effects of deficiency in the DNA mismatch repair (MMR) protein Pms2 were investigated using the endogenous mouse Hprt and Tk genes as reporters of intragenic mutation and loss of heterozygosity (LOH). Pms2–/–Tk+/–, Pms2+/+Tk+/–, Pms2+/–Tk+/– and Pms2–/–Tk–/– mice were bred from Pms2+/–Tk+/– mice. At 2 months of age, the body weight and splenic T lymphocyte yields were significantly lower in Pms2–/–Tk–/– mice than in littermates of the other genotypes. The mice were evaluated for their spontaneous mutant frequencies in the Hprt and Tk genes of splenic lymphocytes and their frequency of micronuclei in polychromatic erythrocytes from bone marrow. The cloning efficiency of lymphocytes derived from Pms2–/–Tk–/– animals was 12-fold lower than that of animals of the other genotypes. Compared with Pms2+/+ and Pms2+/– mice, Pms2–/– mice had a 21- to 69-fold increase in the Hprt mutant frequency. The Hprt mutant frequency was equally high in Pms2-deficient, Tk+/– and Tk–/– mice. No significant Pms2-dependent change in mutant frequency was detected using the Tk mutational target. When individual Tk mutants were analyzed for LOH mutation by allele-specific genotyping, the fraction of LOH mutants was lower in Pms2-deficient than in Pms2-proficient mice (29.2 and 43.6%, respectively). The frequency of bone marrow micronuclei was significantly higher in Pms2–/–Tk–/– mice than in Pms2–/–Tk+/– mice. These observations suggest that the simultaneous occurrence of Tk and Pms2 deficiencies may cause a decrease in cell viability that diminishes the Tk mutational response, making it impossible to discern clearly the effect of Pms2 deficiency on LOH-type mutation using the Tk reporter system. The interaction between Tk deficiency and a component of the MMR system suggests that Tk-deficient cells may have higher levels of DNA polymerase misincorporation or endogenous DNA damage than Tk-proficient cells.
1To whom correspondence should be addressed. Tel: +1 870 543 7946; Fax: +1 870 543 7393; Email: bparsons{at}nctr.fda.gov
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