Trends in Molecular Medicine
ReviewMouse models for human DNA mismatch-repair gene defects
Section snippets
Msh2-mutant mice
Three different Msh2 mouse lines with inactivating Msh2 mutations have been reported 15., 16., 17. (Table 1). Msh2-deficient mice developed normally and both male and female mice were fertile. However, Msh2 deficiency caused a significant reduction in the survival of the mice. Whereas heterozygous Msh2+/− mutant mice were indistinguishable from wild-type mice, 50% of the homozygous Msh2−/− mutant mice died by six months of age and all animals were reported dead by 12 months of age [18].
The
Mlh1-mutant mice
Mouse lines deficient in Mlh1 were generated by three groups 34., 35., 36.. Although heterozygous and homozygous Mlh1 mice are viable, the Mlh1−/− mice have reduced survival compared with Mlh1+/− and wild-type littermates. In a manner similar to Msh2−/− mice, 50% of the Mlh1−/− mice died by six months of age and all of the animals were dead by 12 months 37., 38.. The mice developed a spectrum of tumors that resembled the tumor spectrum of the Msh2-mutant mice, including T-cell lymphomas, GI
The role of MMR genes in Apc-driven tumorigenesis
Defects in MMR result in the accumulation of DNA replication errors throughout the genome as indicated by MSI. If such errors occur in the coding region of key tumor suppressor genes and oncogenes that control cell growth and differentiation, they can lead to tumor development. Indeed, in many MSI-positive colorectal tumors, frameshift mutations within short mononucleotide repeat sequences (coding microsatellites) were observed in the coding region of tumor suppressor genes such as APC, TGF-βRII
Response to DNA-damaging agents in MMR-mutant mice
Treatment of MMR-deficient cell lines with DNA-damaging agents revealed that MMR plays a role in the processing of chemically damaged DNA. Cytotoxic alkylating agents such as N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU) introduce O6-methyl-guanine (O6MeG) into DNA. Tumors cell lines deficient in MSH2, MSH6, MLH1 and PMS2 were resistant to the killing by these alkylating agents as well as other DNA-damaging agents such as 6-thioguanine (6-TG), cisplatin and
MMR-mutant mouse lines as preclinical models
The MMR mouse lines described above are also suitable in vivo models to evaluate the role of chemopreventive and therapeutic agents on tumorigenesis. In two recent studies, the preventive effect of nonsteroidal anti-inflammatory drugs (NSAIDs) was tested in Msh2−/− and Msh2−/−ApcMin/+ mouse lines [57]. Long-term exposure to aspirin showed only a small increase in the survival of Msh2−/− mice and appeared to have no effect on the development of lymphomas. In addition, aspirin exposure did not
MMR-mutant mouse lines as models for HNPCC
The analysis of the MMR-mutant mice demonstrated that, as in humans, inactivation of Msh2 and Mlh1 in mice leads to a strong cancer syndrome with high penetrance. The inactivation of Msh6 and Pms2 resulted in a less severe cancer phenotype and late onset of GI tumors in Msh6−/− mice. In general, the cancer phenotypes in MMR-mutant mice correlate well with their corresponding repair defects. However, there are differences between the human and mouse phenotypes. First, HNPCC patients are
Concluding remarks
The availability of mouse lines with inactivating mutations in each of the different mutS and mutL genes has allowed a detailed assessment of the consequences of complete inactivation of each gene for MMR and has also defined their biological functions as well as their individual importance for the suppression of cancer. Although there are species-specific differences in the cancer phenotypes, the MMR functions are well conserved. The MMR mouse models offer an opportunity to determine the
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