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Gene Review

MSH6  -  mismatch repair ATPase MSH6

Saccharomyces cerevisiae S288c

Synonyms: DNA mismatch repair protein MSH6, MutS protein homolog 6, PMS3, PMS6, Postmeiotic segregation protein 3, ...
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Disease relevance of MSH6

  • Using this approach, we have successfully produced high-milligram quantities of two different Saccharomyces cerevisiae complexes in E. coli: the heterodimeric Msh2-Msh6 mismatch repair protein (248kDa) and the five-subunit replication factor C clamp loader (250 kDa) [1].
  • Previous analyses of both Thermus aquaticus MutS homodimer and Saccharomyces cerevisiae Msh2-Msh6 heterodimer have revealed that the subunits in these protein complexes bind and hydrolyze ATP asymmetrically, emulating their asymmetric DNA binding properties [2].

High impact information on MSH6

  • An msh6 mutation that eliminated the PCNA-binding site caused a mutator phenotype and a defect in the interaction with PCNA [3].
  • Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex [3].
  • In mlh1 Delta strains, heteroduplex rejection was greater than in msh6 Delta strains but less than in wild type [4].
  • Combination of mutations in MLH3 and MSH6 caused a synergistic increase in the hom3-10 reversion rate, whereas the hom3-10 reversion rate in an mlh3 msh3 double mutant was the same as in the respective single mutants [5].
  • In addition, analysis of the +1 spectra revealed novel roles for Msh3p and Msh6p in removing specific types of frameshift intermediates [6].

Biological context of MSH6

  • In yeast, MSH2 interacts with MSH6 to repair base pair mismatches and single nucleotide insertion/deletion mismatches and with MSH3 to recognize small loop insertion/deletion mismatches [7].
  • Genetic analysis suggested that this phenotype was due to msh6-F337A sequestering MSH2 and preventing it from interacting with MSH3 and MSH6 [7].
  • The Saccharomyces cerevisiae mismatch repair (MMR) protein MSH6 and the SGS1 helicase were recently shown to play similarly important roles in preventing recombination between divergent DNA sequences in a single-strand annealing (SSA) assay [8].
  • Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability [9].
  • To understand early steps in mismatch repair, we analyzed mismatch repair (MMR) defective MSH2-msh6-F337A and MSH2-msh6-340 complexes that contained amino acid substitutions in the MSH6 mismatch recognition domain [10].

Associations of MSH6 with chemical compounds


Regulatory relationships of MSH6

  • This reduction in heteroduplex rejection was suppressed in a mismatch repair-defective msh6 Delta strain and partially suppressed in an msh2 separation-of-function mutant [4].

Other interactions of MSH6

  • The pol30-204 mutation altered an amino acid (C81R) in the monomer-monomer interface region and resulted in a partial general MMR defect and a defect in MSH2-MSH6 binding in vitro [16].
  • Disruption of the MSH3 or MSH6 genes (also MUTS homologues) resulted in elevation of the mutation frequency and rate, but to a lesser degree than that caused by the inactivation of MSH2 [17].

Analytical, diagnostic and therapeutic context of MSH6


  1. Overproduction and analysis of eukaryotic multiprotein complexes in Escherichia coli using a dual-vector strategy. Finkelstein, J., Antony, E., Hingorani, M.M., O'Donnell, M. Anal. Biochem. (2003) [Pubmed]
  2. Contribution of Msh2 and Msh6 subunits to the asymmetric ATPase and DNA mismatch binding activities of Saccharomyces cerevisiae Msh2-Msh6 mismatch repair protein. Antony, E., Khubchandani, S., Chen, S., Hingorani, M.M. DNA Repair (Amst.) (2006) [Pubmed]
  3. Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex. Flores-Rozas, H., Clark, D., Kolodner, R.D. Nat. Genet. (2000) [Pubmed]
  4. Heteroduplex rejection during single-strand annealing requires Sgs1 helicase and mismatch repair proteins Msh2 and Msh6 but not Pms1. Sugawara, N., Goldfarb, T., Studamire, B., Alani, E., Haber, J.E. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  5. The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations. Flores-Rozas, H., Kolodner, R.D. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  6. Removal of frameshift intermediates by mismatch repair proteins in Saccharomyces cerevisiae. Harfe, B.D., Jinks-Robertson, S. Mol. Cell. Biol. (1999) [Pubmed]
  7. A mutation in the MSH6 subunit of the Saccharomyces cerevisiae MSH2-MSH6 complex disrupts mismatch recognition. Bowers, J., Sokolsky, T., Quach, T., Alani, E. J. Biol. Chem. (1999) [Pubmed]
  8. Distinct roles for the Saccharomyces cerevisiae mismatch repair proteins in heteroduplex rejection, mismatch repair and nonhomologous tail removal. Goldfarb, T., Alani, E. Genetics (2005) [Pubmed]
  9. Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability. Johnson, R.E., Kovvali, G.K., Prakash, L., Prakash, S. J. Biol. Chem. (1996) [Pubmed]
  10. Analysis of yeast MSH2-MSH6 suggests that the initiation of mismatch repair can be separated into discrete steps. Bowers, J., Tran, P.T., Liskay, R.M., Alani, E. J. Mol. Biol. (2000) [Pubmed]
  11. MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S. cerevisiae. Ni, T.T., Marsischky, G.T., Kolodner, R.D. Mol. Cell (1999) [Pubmed]
  12. ATP-dependent assembly of a ternary complex consisting of a DNA mismatch and the yeast MSH2-MSH6 and MLH1-PMS1 protein complexes. Habraken, Y., Sung, P., Prakash, L., Prakash, S. J. Biol. Chem. (1998) [Pubmed]
  13. Saccharomyces cerevisiae MSH2-MSH3 and MSH2-MSH6 Complexes Display Distinct Requirements for DNA Binding Domain I in Mismatch Recognition. Lee, S.D., Surtees, J.A., Alani, E. J. Mol. Biol. (2007) [Pubmed]
  14. Cadmium inhibits mismatch repair by blocking the ATPase activity of the MSH2-MSH6 complex. Banerjee, S., Flores-Rozas, H. Nucleic Acids Res. (2005) [Pubmed]
  15. Asymmetric recognition of DNA local distortion. Structure-based functional studies of eukaryotic Msh2-Msh6. Drotschmann, K., Yang, W., Brownewell, F.E., Kool, E.T., Kunkel, T.A. J. Biol. Chem. (2001) [Pubmed]
  16. Isolation and characterization of new proliferating cell nuclear antigen (POL30) mutator mutants that are defective in DNA mismatch repair. Lau, P.J., Flores-Rozas, H., Kolodner, R.D. Mol. Cell. Biol. (2002) [Pubmed]
  17. The influence of the mismatch-repair system on stationary-phase mutagenesis in the yeast Saccharomyces cerevisiae. Hałas, A., Baranowska, H., Policińska, Z. Curr. Genet. (2002) [Pubmed]
  18. Biochemical characterization of the interaction between the Saccharomyces cerevisiae MSH2-MSH6 complex and mispaired bases in DNA. Marsischky, G.T., Kolodner, R.D. J. Biol. Chem. (1999) [Pubmed]
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