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Gene Review

Msh2  -  mutS homolog 2 (E. coli)

Mus musculus

Synonyms: AI788990, DNA mismatch repair protein Msh2, MutS protein homolog 2
 
 
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Disease relevance of Msh2

  • In contrast, adenomas from Msh2 deficient Min (Apc+/-Msh2-/-) mice are not usually associated with LOH [1].
  • Most of the completely Msh2-deficient mice succumbed to lymphomas at an early age; lymphomagenesis was synergistically enhanced by exposure to ethylnitrosourea [2].
  • Mice with a single wild-type Rb allele develop a syndrome of multiple neuroendocrine neoplasia, and inactivation of both alleles of Msh2 gene predisposes mice to gastrointestinal cancer, lymphomas and tumors of the skin that exhibit a mismatch repair defect [3].
  • The mutation rate of the herpes simplex virus thymidine kinase 1 (HSV-tk1) gene was unchanged in Msh3-deficient ES cell lines but markedly elevated in Msh2-deficient and Msh3 Msh2 double-mutant cells [4].
  • Here we describe the application of the DSS model of chronic colitis to mice with a defect in the Msh2 mismatch repair gene to discern these early events [5].
  • In the large intestine, very few adenomas were found in Msh2(-/-) mice (0.13 per mouse) whereas K-ras(V12)/Cre/Msh2(-/-) mice produced 2.70 adenomas per mouse (increased 20-fold, P<0.01) [6].
 

High impact information on Msh2

  • Our data support a model in which expansion in the germ cells arises by gap repair and depends on a complex containing Msh2 [7].
  • No female embryonic lethality in mice nullizygous for Msh2 and p53 [8].
  • Mice that are deficient in either the Pms2 or Msh2 DNA mismatch repair genes have microsatellite instability and a predisposition to tumours [9].
  • Msh2-deficient mice display no major abnormalities, but a significant fraction develops lymphomas at an early age [10].
  • Msh2-deficient cells have lost mismatch binding and have acquired microsatellite instability, a mutator phenotype, and tolerance to methylating agents [10].
 

Biological context of Msh2

 

Anatomical context of Msh2

 

Associations of Msh2 with chemical compounds

  • Msh2 deficiency reduced the apoptotic response to each agent, but only led to increased crypt survival after NMNU treatment [12].
  • Apoptosis and long term enterocyte survival were examined in vivo after exposure to three cytotoxic agents (Cisplatin, Nitrogen Mustard and N-methyl-N-nitrosourea (NMNU/MNU)) within mice either singly or doubly mutant for p53 and Msh2 [12].
  • Compared with wild-type mice, Msh2-deficient animals had higher basal levels of mutation and were more sensitive to the mutagenic effects of temozolomide [15].
  • To further dissect the role of Msh2 in SHM and CSR, mice with a "knockin" mutation in the Msh2 gene that inactivates the adenosine triphosphatase domain were examined [16].
  • To examine the role of the MSH2 mismatch repair protein in hypermutation, Msh2-/- mice were immunized with oxazolone, and B cells were analyzed for mutation in their VkappaOx1 light chain genes [17].
 

Regulatory relationships of Msh2

  • Heterozygosity for p53 promotes microsatellite instability and tumorigenesis on a Msh2 deficient background [18].
  • Furthermore, some Msh2 null clones expressed high levels of Rad51 specifically, a critical component of HRR [19].
  • We next compared this mutability preference with those in hypermutating Ramos cells and in msh2(-/-)ung(-/-) mice, since both are reduced or deficient in UNG- and/or Msh2-induced mutations and are thus likely to reflect the sequence specificity of the mutator in vivo [20].
 

Other interactions of Msh2

  • Mlh1 can function in antibody class switch recombination independently of Msh2 [11].
  • The association of MLH3 with repetitive DNA sequences is coincident with MSH2-MSH3 and is decreased in Msh2-/- and Msh3-/- mice, suggesting a novel role for the MMR family in the maintenance of repeat unit integrity during mammalian meiosis [21].
  • Deficiencies in Ung, Msh2, or Msh6 affect SHM and CSR [22].
  • This suggests that Msh2 may play a role in repairing activation-induced cytidine deaminase-generated G-U mismatches [16].
  • Likewise, the decrease in erythrocyte counts was more prominent in mice with at least one functional Msh2 allele [23].
 

Analytical, diagnostic and therapeutic context of Msh2

References

  1. Msh2 deficiency enhances somatic Apc and p53 mutations in Apc+/-Msh2-/- mice. Sohn, K.J., Choi, M., Song, J., Chan, S., Medline, A., Gallinger, S., Kim, Y.I. Carcinogenesis (2003) [Pubmed]
  2. Mouse models for hereditary nonpolyposis colorectal cancer. de Wind, N., Dekker, M., van Rossum, A., van der Valk, M., te Riele, H. Cancer Res. (1998) [Pubmed]
  3. Cell lineage-specific effects associated with multiple deficiencies of tumor susceptibility genes in Msh2(-/-)Rb(+/-) mice. Nikitin, A.Y., Liu, C.Y., Flesken-Nikitin, A., Chen, C.F., Chen, P.L., Lee, W.H. Cancer Res. (2002) [Pubmed]
  4. Genetic analysis of mouse embryonic stem cells bearing Msh3 and Msh2 single and compound mutations. Abuin, A., Zhang, H., Bradley, A. Mol. Cell. Biol. (2000) [Pubmed]
  5. Susceptibility of Msh2-deficient mice to inflammation-associated colorectal tumors. Kohonen-Corish, M.R., Daniel, J.J., te Riele, H., Buffinton, G.D., Dahlstrom, J.E. Cancer Res. (2002) [Pubmed]
  6. Conditional expression of mutated K-ras accelerates intestinal tumorigenesis in Msh2-deficient mice. Luo, F., Brooks, D.G., Ye, H., Hamoudi, R., Poulogiannis, G., Patek, C.E., Winton, D.J., Arends, M.J. Oncogene (2007) [Pubmed]
  7. Trinucleotide expansion in haploid germ cells by gap repair. Kovtun, I.V., McMurray, C.T. Nat. Genet. (2001) [Pubmed]
  8. No female embryonic lethality in mice nullizygous for Msh2 and p53. Toft, N.J., Arends, M.J., Wyllie, A.H., Clarke, A.R. Nat. Genet. (1998) [Pubmed]
  9. Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Baker, S.M., Plug, A.W., Prolla, T.A., Bronner, C.E., Harris, A.C., Yao, X., Christie, D.M., Monell, C., Arnheim, N., Bradley, A., Ashley, T., Liskay, R.M. Nat. Genet. (1996) [Pubmed]
  10. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. de Wind, N., Dekker, M., Berns, A., Radman, M., te Riele, H. Cell (1995) [Pubmed]
  11. Mlh1 can function in antibody class switch recombination independently of Msh2. Schrader, C.E., Vardo, J., Stavnezer, J. J. Exp. Med. (2003) [Pubmed]
  12. The ability to engage enterocyte apoptosis does not predict long-term crypt survival in p53 and Msh2 deficient mice. Sansom, O.J., Clarke, A.R. Oncogene (2002) [Pubmed]
  13. Mismatch repair protein Msh2 contributes to UVB-induced cell cycle arrest in epidermal and cultured mouse keratinocytes. van Oosten, M., Stout, G.J., Backendorf, C., Rebel, H., de Wind, N., Darroudi, F., van Kranen, H.J., de Gruijl, F.R., Mullenders, L.H. DNA Repair (Amst.) (2005) [Pubmed]
  14. Different mismatch repair deficiencies all have the same effects on somatic hypermutation: intact primary mechanism accompanied by secondary modifications. Kim, N., Bozek, G., Lo, J.C., Storb, U. J. Exp. Med. (1999) [Pubmed]
  15. Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine. Toft, N.J., Winton, D.J., Kelly, J., Howard, L.A., Dekker, M., te Riele, H., Arends, M.J., Wyllie, A.H., Margison, G.P., Clarke, A.R. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  16. Msh2 ATPase activity is essential for somatic hypermutation at a-T basepairs and for efficient class switch recombination. Martin, A., Li, Z., Lin, D.P., Bardwell, P.D., Iglesias-Ussel, M.D., Edelmann, W., Scharff, M.D. J. Exp. Med. (2003) [Pubmed]
  17. Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein. Phung, Q.H., Winter, D.B., Cranston, A., Tarone, R.E., Bohr, V.A., Fishel, R., Gearhart, P.J. J. Exp. Med. (1998) [Pubmed]
  18. Heterozygosity for p53 promotes microsatellite instability and tumorigenesis on a Msh2 deficient background. Toft, N.J., Curtis, L.J., Sansom, O.J., Leitch, A.L., Wyllie, A.H., te Riele, H., Arends, M.J., Clarke, A.R. Oncogene (2002) [Pubmed]
  19. Deregulation of homologous recombination DNA repair in alkylating agent-treated stem cell clones: a possible role in the aetiology of chemotherapy-induced leukaemia. Worrillow, L.J., Allan, J.M. Oncogene (2006) [Pubmed]
  20. The mutation spectrum of purified AID is similar to the mutability index in Ramos cells and in ung(-/-)msh2(-/-) mice. Larijani, M., Frieder, D., Basit, W., Martin, A. Immunogenetics (2005) [Pubmed]
  21. Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I. Kolas, N.K., Svetlanov, A., Lenzi, M.L., Macaluso, F.P., Lipkin, S.M., Liskay, R.M., Greally, J., Edelmann, W., Cohen, P.E. J. Cell Biol. (2005) [Pubmed]
  22. Somatic hypermutation and class switch recombination in msh6-/-ung-/- double-knockout mice. Shen, H.M., Tanaka, A., Bozek, G., Nicolae, D., Storb, U. J. Immunol. (2006) [Pubmed]
  23. Msh2 deficiency attenuates but does not abolish thiopurine hematopoietic toxicity in msh2-/- mice. Krynetskaia, N.F., Brenner, T.L., Krynetski, E.Y., Du, W., Panetta, J.C., Ching-Hon, P., Evans, W.E. Mol. Pharmacol. (2003) [Pubmed]
  24. Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions. Schrader, C.E., Vardo, J., Stavnezer, J. J. Exp. Med. (2002) [Pubmed]
  25. Mitochondrial dysfunction and increased sensitivity to excitotoxicity in mice deficient in DNA mismatch repair. Francisconi, S., Codenotti, M., Toninelli, G.F., Uberti, D., Memo, M. J. Neurochem. (2006) [Pubmed]
 
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