Carcinogenesis, Vol. 21, No. 7, 1291-1296,
July 2000
© 2000 Oxford University Press
Cancer Biology |
Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts
Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7 Canada,
1 Departments of Therapeutic Radiology and Genetics, Yale University School of Medicine, Boyer Center Room 354, 295 Congress Avenue, New Haven, CT 06536-0812, USA,
2 Centre for Molecular Medicine and Therapeutics and Department of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4 Canada and
3 Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, OR 97201-3098, USA
DNA mismatch repair (MMR) deficiency leads to an increased mutation frequency and a predisposition to neoplasia. `Knockout' mice deficient in the MMR proteins Msh2 and Pms2 crossed with mutation detection reporter (supF, lacI and cII) transgenic mice have been used to facilitate a comparison of the changes in mutation frequency and spectra. We find that the mutation frequency was consistently higher in Msh2-deficient mice than Pms2-deficient mice. The lacI target gene, which is highly sensitive to point mutations, demonstrated that both Msh2- and Pms2-deficient mice accumulate transition mutations as the predominant mutation. However, when compared with Msh2–/– mice, lacI and cII mutants from Pms2-deficient mice revealed an increased proportion of +/–1 bp frameshift mutations and a corresponding decrease in transversion mutations. The supF target gene, which is sensitive to frameshift mutations, and the cII target gene revealed a strong tendency for –1 bp deletions over +1 bp insertions in Msh2–/– compared with Pms2–/– mice. These data indicate that Msh2 and Pms2 deficiency have subtle but differing effects on mutation avoidance which may contribute to the differences in tumor spectra observed in the two `knockout' mouse models. These variances in mutation accumulation may also play a role, in part, in the differences seen in prevalence of MSH2 and PMS2 germline mutations in hereditary non-polyposis colorectal cancer patients.
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