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

DNA mismatch repair (MMR) deficiency leads to an increased mutation frequen cy 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 freque ncy was consistently higher in Msh2-deficient mice than Pms2-deficient mice . The lacI target gene, which is highly sensitive to point mutations, demon strated that both Msh2- and Pms2-deficient mice accumulate transition mutat ions as the predominant mutation. However, when compared with Msh2(-/-) mic e, lacI and cII mutants from Pms2-deficient mice revealed an increased prop ortion of +/-1 bp frameshift mutations and a corresponding decrease in tran sversion mutations. The supF target gene, which is sensitive to frameshift mutations, and the cll target gene revealed a strong tendency for -1 bp del etions over +1 bp insertions in Msh2(-/-) compared with Pms2(-/-) mice. The se data indicate that Msh2 and Pms2 deficiency have subtle but differing ef fects on mutation avoidance which may contribute to the differences in tumo r spectra observed in the two 'knockout' mouse models, These variances In m utation accumulation may also play a role, in part, in the differences seen in prevalence of MSH2 and PMS2 germline mutations in hereditary non-polypo sis colorectal cancer patients.