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Gene Review

Msh6  -  mutS homolog 6 (E. coli)

Mus musculus

Synonyms: AU044881, AW550279, DNA mismatch repair protein Msh6, G/T mismatch-binding protein, GTBP, ...
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Disease relevance of Msh6

  • Msh6-deficient mice were prone to cancer; most animals developed lymphomas or epithelial tumours originating from the skin and uterus but only rarely from the intestine [1].
  • Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins [2].
  • These data support a role for Msh6 in protective cellular responses of primary cells to ultraviolet-B-induced mutagenesis and, hence, the prevention of skin cancer [3].
  • Thus, although the CBP SID domain adopts a similar fold in complex with different p160 proteins, the topologies of the AD1 domains are strikingly different, a feature that is likely to contribute to functional specificity of these coactivator complexes [4].
  • Preclinical evaluation of the breast cancer cell-binding peptide, p160 [5].

High impact information on Msh6

  • These results suggest that GTBP is important for maintaining the integrity of the human genome and document molecular defects accounting for variation in mutator phenotype [6].
  • Endogenous CoCoA was found simultaneously with p160 coactivators on the promoter of an endogenous estrogen-responsive gene [7].
  • Here we show that Msh6(-)(/)(-) mice have a decrease in CSR, whereas Msh3(-)(/)(-) mice do not [8].
  • Together, our data suggest that MutS homologues Msh2, Msh3, and Msh6 play overlapping and distinct roles during antibody diversification processes [8].
  • Examination of Msh6- and Msh3-deficient mice in class switching reveals overlapping and distinct roles of MutS homologues in antibody diversification [8].

Biological context of Msh6

  • Our analysis therefore has revealed distinct mutational spectra and clarified the roles of Msh3 and Msh6 in DNA repair and intestinal tumorigenesis [9].
  • Mice with a mutation in the Msh6 gene have a defect in base mismatch repair and show a tumor predisposition phenotype [10].
  • Msh6-deficient mice had fewer substitutions of A and T bases in both regions and reduced heavy chain class switching, whereas Msh3-deficient mice had normal antibody responses [11].
  • To this end, Big Blue( trade mark ) mice, that carry a lacI(+) transgenic lambda shuttle-phage mutational reporter, were crossed with Msh6(-/-) mice to evaluate the specific contribution of MutS(alpha) to genome integrity [12].
  • Mutational-reporter transgenes rescued from mice lacking either Mgmt, or both Mgmt and Msh6 suggest that O6-alkylguanine-induced miscoding does not contribute to the spontaneous mutational spectrum [13].

Anatomical context of Msh6

  • Elevated mutant frequencies and predominance of G:C to A:T transition mutations in Msh6(-/-) small intestinal epithelium [12].
  • Consistent with the importance of MutS(alpha) in lesion surveillance, small intestine epithelial cell DNA derived from lacI(+) Msh6(-/-) mice exhibited striking increases (average of 41-fold) in spontaneous mutant frequencies [12].
  • Msh6-/- mouse embryonic fibroblasts were significantly less sensitive to the cytotoxic effects of ultraviolet B radiation [3].
  • FGF-1-stimulated NIH 3T3 cells also express an increased amount of GTBP as determined by immunoblot analysis [14].
  • Anti-IgR stimulation induces the increase of the kinase activity coprecipitated with the p160 protein in mature B cell BAL17 and normal adult spleen B cells [15].

Associations of Msh6 with chemical compounds


Physical interactions of Msh6

  • To determine whether Msh2/Msh6 complexes which recognize single-base mismatches and loops were the only mismatch-recognition complexes required for SHM and CSR, we analyzed these processes in Msh6(-/-)Ung(-/-) mice [20].

Other interactions of Msh6

  • However, when Msh3 deficiency is combined with Msh6 deficiency (Msh3(-/-)Msh6(-/-)Apc1638N), the survival rate of the mice was further reduced compared to Msh6(-/-)Apc(1638N) mice because of a high multiplicity of intestinal tumors at a younger age [9].
  • Apc mutations in Msh6(-/-)Apc1638N mice consisted predominantly of base substitutions (93%) creating stop codons, consistent with a major role for Msh6 in the repair of base-base mismatches [9].
  • Deficiencies in Ung, Msh2, or Msh6 affect SHM and CSR [20].
  • Steroid receptor coactivator (SRC)-3, also called amplified in breast cancer 1, is a member of the p160 nuclear receptor coactivator family involved in transcriptional regulation of target genes [21].
  • To optimize our ability to detect mutations resulting from O6-alkylguanine-induced G : T mismatches, mice with combined deficiencies of Mgmt and the DNA mismatch repair molecule, Msh6, were analysed [13].

Analytical, diagnostic and therapeutic context of Msh6

  • Mice carrying a null mutation in the mismatch repair gene Msh6 were generated by gene targeting [22].
  • We now describe the molecular cloning of cDNA corresponding to murine p160 [23].
  • Unexpectedly, immunofluorescence studies show that p160 is localized predominantly in the nucleolus [23].
  • Among the p160/steroid receptor co-activators, only p/CIP (nuclear co-activator 3) has been shown to be up-regulated by interleukin (IL)-4 in B cells through a STAT-6-dependent mechanism using Gene-Chip analysis [24].
  • Sequential immunoprecipitation demonstrated that both p160 and p130 had determinants from two separate regions of the putative bcr translated sequence [25].


  1. HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. de Wind, N., Dekker, M., Claij, N., Jansen, L., van Klink, Y., Radman, M., Riggins, G., van der Valk, M., van't Wout, K., te Riele, H. Nat. Genet. (1999) [Pubmed]
  2. Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins. van den Broek, W.J., Nelen, M.R., Wansink, D.G., Coerwinkel, M.M., te Riele, H., Groenen, P.J., Wieringa, B. Hum. Mol. Genet. (2002) [Pubmed]
  3. DNA mismatch repair protein Msh6 is required for optimal levels of ultraviolet-B-induced apoptosis in primary mouse fibroblasts. Young, L.C., Peters, A.C., Maeda, T., Edelmann, W., Kucherlapati, R., Andrew, S.E., Tron, V.A. J. Invest. Dermatol. (2003) [Pubmed]
  4. Structural diversity in p160/CREB-binding protein coactivator complexes. Waters, L., Yue, B., Veverka, V., Renshaw, P., Bramham, J., Matsuda, S., Frenkiel, T., Kelly, G., Muskett, F., Carr, M., Heery, D.M. J. Biol. Chem. (2006) [Pubmed]
  5. Preclinical evaluation of the breast cancer cell-binding peptide, p160. Askoxylakis, V., Zitzmann, S., Mier, W., Graham, K., Krämer, S., von Wegner, F., Fink, R.H., Schwab, M., Eisenhut, M., Haberkorn, U. Clin. Cancer Res. (2005) [Pubmed]
  6. Mutations of GTBP in genetically unstable cells. Papadopoulos, N., Nicolaides, N.C., Liu, B., Parsons, R., Lengauer, C., Palombo, F., D'Arrigo, A., Markowitz, S., Willson, J.K., Kinzler, K.W. Science (1995) [Pubmed]
  7. CoCoA, a nuclear receptor coactivator which acts through an N-terminal activation domain of p160 coactivators. Kim, J.H., Li, H., Stallcup, M.R. Mol. Cell (2003) [Pubmed]
  8. Examination of Msh6- and Msh3-deficient mice in class switching reveals overlapping and distinct roles of MutS homologues in antibody diversification. Li, Z., Scherer, S.J., Ronai, D., Iglesias-Ussel, M.D., Peled, J.U., Bardwell, P.D., Zhuang, M., Lee, K., Martin, A., Edelmann, W., Scharff, M.D. J. Exp. Med. (2004) [Pubmed]
  9. The distinct spectra of tumor-associated Apc mutations in mismatch repair-deficient Apc1638N mice define the roles of MSH3 and MSH6 in DNA repair and intestinal tumorigenesis. Kuraguchi, M., Yang, K., Wong, E., Avdievich, E., Fan, K., Kolodner, R.D., Lipkin, M., Brown, A.M., Kucherlapati, R., Edelmann, W. Cancer Res. (2001) [Pubmed]
  10. Mouse models for colorectal cancer. Heyer, J., Yang, K., Lipkin, M., Edelmann, W., Kucherlapati, R. Oncogene (1999) [Pubmed]
  11. A role for Msh6 but not Msh3 in somatic hypermutation and class switch recombination. Martomo, S.A., Yang, W.W., Gearhart, P.J. J. Exp. Med. (2004) [Pubmed]
  12. Elevated mutant frequencies and predominance of G:C to A:T transition mutations in Msh6(-/-) small intestinal epithelium. Mark, S.C., Sandercock, L.E., Luchman, H.A., Baross, A., Edelmann, W., Jirik, F.R. Oncogene (2002) [Pubmed]
  13. Mutational-reporter transgenes rescued from mice lacking either Mgmt, or both Mgmt and Msh6 suggest that O6-alkylguanine-induced miscoding does not contribute to the spontaneous mutational spectrum. Sandercock, L.E., Kwok, M.C., Luchman, H.A., Mark, S.C., Giesbrecht, J.L., Samson, L.D., Jirik, F.R. Oncogene (2004) [Pubmed]
  14. Fibroblast growth factor-1 stimulation of quiescent NIH 3T3 cells increases G/T mismatch-binding protein expression. Donohue, P.J., Feng, S.L., Alberts, G.F., Guo, Y., Peifley, K.A., Hsu, D.K., Winkles, J.A. Biochem. J. (1996) [Pubmed]
  15. B cell Ag receptor mediates different types of signals in the protein kinase activity between immature B cell and mature B cell. Igarashi, H., Kuwahara, K., Nomura, J., Matsuda, A., Kikuchi, K., Inui, S., Sakaguchi, N. J. Immunol. (1994) [Pubmed]
  16. Partially redundant functions of SRC-1 and TIF2 in postnatal survival and male reproduction. Mark, M., Yoshida-Komiya, H., Gehin, M., Liao, L., Tsai, M.J., O'Malley, B.W., Chambon, P., Xu, J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  17. Interleukin-6 signals activating junB and TIS11 gene transcription in a B-cell hybridoma. Nakajima, K., Wall, R. Mol. Cell. Biol. (1991) [Pubmed]
  18. Inhibition of estrogen receptor alpha-mediated transcription by antiestrogenic 1,1-dichloro-2,2,3-triarylcyclopropanes. Cheng, P., Kanterewicz, B., Hershberger, P.A., McCarty, K.S., Day, B.W., Nichols, M. Mol. Pharmacol. (2004) [Pubmed]
  19. Characterization and development of a peptide (p160) with affinity for neuroblastoma cells. Askoxylakis, V., Mier, W., Zitzmann, S., Ehemann, V., Zhang, J., Krämer, S., Beck, C., Schwab, M., Eisenhut, M., Haberkorn, U. J. Nucl. Med. (2006) [Pubmed]
  20. 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]
  21. Steroid Receptor Coactivator-3 and Activator Protein-1 Coordinately Regulate the Transcription of Components of the Insulin-Like Growth Factor/AKT Signaling Pathway. Yan, J., Yu, C.T., Ozen, M., Ittmann, M., Tsai, S.Y., Tsai, M.J. Cancer Res. (2006) [Pubmed]
  22. Mutation in the mismatch repair gene Msh6 causes cancer susceptibility. Edelmann, W., Yang, K., Umar, A., Heyer, J., Lau, K., Fan, K., Liedtke, W., Cohen, P.E., Kane, M.F., Lipford, J.R., Yu, N., Crouse, G.F., Pollard, J.W., Kunkel, T., Lipkin, M., Kolodner, R., Kucherlapati, R. Cell (1997) [Pubmed]
  23. Molecular cloning reveals that the p160 Myb-binding protein is a novel, predominantly nucleolar protein which may play a role in transactivation by Myb. Tavner, F.J., Simpson, R., Tashiro, S., Favier, D., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., Macmillan, E.M., Lutwyche, J., Keough, R.A., Ishii, S., Gonda, T.J. Mol. Cell. Biol. (1998) [Pubmed]
  24. The transcriptional co-activator p/CIP (NCoA-3) is up-regulated by STAT6 and serves as a positive regulator of transcriptional activation by STAT6. Arimura, A., vn Peer, M., Schröder, A.J., Rothman, P.B. J. Biol. Chem. (2004) [Pubmed]
  25. Identification of two normal bcr gene products in the cytoplasm. Dhut, S., Dorey, E.L., Horton, M.A., Ganesan, T.S., Young, B.D. Oncogene (1988) [Pubmed]
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