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, Robert (Mike) Liskay, Frank R. Jirik, Peter M. Glazer

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1291-1295
Number of pages5
JournalCarcinogenesis
Volume21
Issue number7
StatePublished - 2000

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Mutagenesis
Mutation Rate
Mutation
Frameshift Mutation
DNA Mismatch Repair
Knockout Mice
DNA Repair-Deficiency Disorders
Genes
Germ-Line Mutation
Point Mutation
Transgenic Mice
Colorectal Neoplasms
Neoplasms
Proteins

ASJC Scopus subject areas

  • Cancer Research

Cite this

Andrew, S. E., Xu, X. S., Baross-Francis, A., Narayanan, L., Milhausen, K., Liskay, R. M., ... Glazer, P. M. (2000). Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts. Carcinogenesis, 21(7), 1291-1295.

Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts. / Andrew, Susan E.; Xu, Xiaoxin S.; Baross-Francis, Agnes; Narayanan, Latha; Milhausen, Kate; Liskay, Robert (Mike); Jirik, Frank R.; Glazer, Peter M.

In: Carcinogenesis, Vol. 21, No. 7, 2000, p. 1291-1295.

Research output: Contribution to journalArticle

Andrew, SE, Xu, XS, Baross-Francis, A, Narayanan, L, Milhausen, K, Liskay, RM, Jirik, FR & Glazer, PM 2000, 'Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts', Carcinogenesis, vol. 21, no. 7, pp. 1291-1295.
Andrew SE, Xu XS, Baross-Francis A, Narayanan L, Milhausen K, Liskay RM et al. Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts. Carcinogenesis. 2000;21(7):1291-1295.
Andrew, Susan E. ; Xu, Xiaoxin S. ; Baross-Francis, Agnes ; Narayanan, Latha ; Milhausen, Kate ; Liskay, Robert (Mike) ; Jirik, Frank R. ; Glazer, Peter M. / Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts. In: Carcinogenesis. 2000 ; Vol. 21, No. 7. pp. 1291-1295.
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