Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent

Abstract

The mutational response of mismatch repair-deficient animals to the alkylating agent N-methyl-N-nitrosourea was evaluated by using a transgenic lacI reporter system. Although the mutations detected in MSH2 heterozygotes were similar to those of controls, MSH2-/- animals demonstrated striking increases in mutation frequency in response to this agent. G:C to A:T transitions at GpG sites, as opposed to CpG sites, dominated the mutational spectrum of both MSH2+/+ and MSH2-/- N-methyl-N-nitrosourea -treated animals. Extrapolating to humans with hereditary non-polyposis colorectal cancer, the results suggest that MSH2 heterozygotes are unlikely to be at increased risk of mutation, even when exposed to potent DNA methylating agents. In contrast, mismatch repair-deficient cells spontaneously arising within individuals with hereditary non-polyposis colorectal cancer would likely exhibit hypermutability in response to such mutagens, an outcome predicted to accelerate the pace of tumorigenesis.

Figure 1

LacI mutation frequencies (and standard errors) from tissues from MSH2^+/+, MSH2^+/−, and MSH2^−/− animals, untreated and treated with MNU.

Figure 2

Flanking sequence of G:C to A:T transitions observed in untreated MSH2^+/+ and MSH2^−/− animals (A) and MNU-treated MSH2^+/+ and MSH2^−/− animals (B).