Journal Article

Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts

Susan E. Andrew, Xiaoxin S. Xu, Agnes Baross-Francis, Latha Narayanan, Kate Milhausen, R.Michael Liskay, Frank R. Jirik and Peter M. Glazer

in Carcinogenesis

Volume 21, issue 7, pages 1291-1296
Published in print July 2000 | ISSN: 0143-3334
Published online July 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.7.1291
Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts

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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.

Keywords: MMR, mismatch repair; HNPCC, hereditary non-polyposis colorectal cancer syndrome.

Journal Article.  4204 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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