Review
Mouse models for human DNA mismatch-repair gene defects

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Abstract

The mammalian DNA mismatch-repair genes belong to a family of genes that comprise several homologs of the Escherichia coli mutS and mutL genes. The observation that mutations in the two human repair genes MSH2 and MLH1 are responsible for hereditary nonpolyposis colorectal cancer, as well as a significant number of sporadic colorectal cancers, raises several questions about the role of these proteins and their family members in the initiation and progression of colorectal cancer. To address these questions, mice with inactivating mutations in all the known mutS and mutL homologs have been generated. The development of these mouse lines has permitted the systematic analysis of the role of each gene in the repair process and has underscored their significance in mutation avoidance and cancer susceptibility. These analyses were critical for our understanding of the function of these genes at the organismal level and also revealed an essential role for some of the DNA mismatch-repair genes in mammalian meiosis.

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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