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

• MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S. cerevisiae [11].
• Addition of ATP or the nonhydrolyzable ATPgammaS reduces binding of the MSH2-MSH6 complex to the DNA substrates markedly [12].
• Saccharomyces cerevisiae MSH2-MSH3 and MSH2-MSH6 Complexes Display Distinct Requirements for DNA Binding Domain I in Mismatch Recognition [13].
• Cadmium inhibits mismatch repair by blocking the ATPase activity of the MSH2-MSH6 complex [14].
• Moreover, wild-type Msh2-Msh6 binds with lower affinity to mismatches with thymine replaced by difluorotoluene, which lacks the ability to hydrogen bond [15].

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

• The interaction of the Saccharomyces cerevisiae MSH2-MSH6 complex with mispaired bases was analyzed using gel mobility shift assays and surface plasmon resonance methods [18].

References