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Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts
S E Andrew1, X S Xu, A Baross-Francis
1Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7 Canada. seandrew@gpu.srv.ualberta.ca
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.
Insights
DNA mismatch repair (MMR) deficiency increases mutation frequency. Msh2 and Pms2 knockout mice show differing mutation spectra, impacting tumor development and hereditary cancer risk.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- DNA mismatch repair (MMR) deficiency is linked to higher mutation rates and cancer predisposition.
- Understanding MMR protein function is crucial for cancer etiology and treatment.
Purpose of the Study:
- To compare mutation frequency and spectra in Msh2-deficient versus Pms2-deficient mice.
- To investigate the distinct roles of Msh2 and Pms2 in DNA mutation avoidance.
Main Methods:
- Utilized 'knockout' mice lacking Msh2 or Pms2, crossed with transgenic reporter mice (supF, lacI, cII).
- Analyzed mutation frequency and types (transitions, transversions, frameshifts) in target genes.
Main Results:
- Msh2-deficient mice exhibited higher mutation frequencies than Pms2-deficient mice.
- Both deficiencies predominantly caused transition mutations, but Pms2 deficiency increased frameshifts, while Msh2 deficiency favored deletions over insertions.
Conclusions:
- Msh2 and Pms2 deficiencies have distinct impacts on mutation avoidance, potentially explaining differences in tumor spectra.
- These mutation variances may contribute to the varying prevalence of MSH2 and PMS2 mutations in hereditary non-polyposis colorectal cancer.