Disease relevance of MSH2

• The MSH1 and MSH2 genes of Saccharomyces cerevisiae are predicted to encode proteins that are homologous to the Escherichia coli MutS and Streptococcus pneumoniae HexA proteins and their homologs [1].
• Germ line DNA mismatch repair mutations in MLH1 and MSH2 underlie the vast majority of hereditary non-polyposis colon cancer [2].
• 'Saccharomyces cerevisiae MSH2/6 complex interacts with Holliday junctions and facilitates their cleavage by phage resolution enzymes [3].
• Mutations in a human homologue of the yeast DNA mismatch repair gene MSH2 (equivalent to bacterial MutS) cause the condition hereditary non-polyposis colorectal cancer (HNPCC) [4].

High impact information on MSH2

• Our results suggest that PCNA functions directly in mispair recognition and that mispair recognition requires a higher-order complex containing proteins in addition to Msh2p-Msh6p [5].
• Using mutations affecting the initiation of recombination (spo11) or mismatch repair (msh2 pms1 ), we demonstrate that meiotic destabilization depends on the initiation of homologous recombination at nearby DNA double-strand break (DSBs) sites and involves a 'rearranged heteroduplex' intermediate [6].
• By examining the PMS patterns in yeast strains heterozygous for a mutant allele with a 26-base-pair insertion, we find that the repair of 26-base loops involves Msh2 (a DNA-mismatch repair protein) and Rad1 (a protein required for nucleotide-excision repair) [7].
• In the yeast Saccharomyces cerevisiae, DNA mismatch repair requires the MSH2, MLH1, and PMS1 proteins [8].
• Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair [9].

Biological context of MSH2

• Removal of one nonhomologous DNA end during gene conversion by a RAD1- and MSH2-independent pathway [10].
• We determined that MSH2, but not MLH1, is transcriptionally regulated during the cell-cycle like PMS1, and that rad3-1 does not increase the transcript levels for these genes in log phase cells [11].
• Subsequently, the pms5-1 mutant allele was shown to be complemented by a plasmid borne yeast MSH2 gene, implying that it is an allele of MSH2 (PMS5) [12].
• The products of the yeast mismatch repair genes MSH2 and MSH3 participate in the inhibition of genetic recombination between homeologous (divergent) DNA sequences [13].
• MSH2 depresses human minisatellite frequency in meiotic cells of yeast [14].

Anatomical context of MSH2

• Protein levels were similar to gene expression patterns, and both PMS2 and MSH2 were localized in spermatogonia and spermatocytes [15].

Associations of MSH2 with chemical compounds

• In one orientation of the homeologous gene pair, msh2 or msh3 mutations resulted in 17- and 9.6-fold elevations in recombination and the msh2 msh3 double mutant exhibited an 43-fold increase, implying that each MSH gene can function independently in trans to prevent homeologous recombination [16].
• MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S. cerevisiae [17].
• Addition of ATP or the nonhydrolyzable ATPgammaS reduces binding of the MSH2-MSH6 complex to the DNA substrates markedly [18].
• Saccharomyces cerevisiae MSH2-MSH3 and MSH2-MSH6 Complexes Display Distinct Requirements for DNA Binding Domain I in Mismatch Recognition [19].
• Haploid msh2 mutants displayed an increase of 85-fold in the rate of spontaneous mutation to canavanine resistance [1].

Physical interactions of MSH2

• Yeast Msh2p forms complexes with Msh3p and Msh6p to repair DNA mispairs that arise during DNA replication [20].
• EXO1 interacts with MSH2 and MLH1 and has been proposed to be a redundant exonuclease that functions in mismatch repair (MMR) [21].
• We propose that the inhibition of conversion by large inserts is due to recognition by the Msh2/Pms1 complex of mismatches created by intrastrand interactions in the heteroduplex loop [22].
• The properties of purified heterodimers suggest that the ATPase active site in Msh6 binds ATP with higher affinity and hydrolyzes ATP faster and with higher efficiency than does the ATPase active site in Msh2 [23].

Regulatory relationships of MSH2

• 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 [24].
• The synthetic lethality between a group A mutant, pol30-104, and rad52 was almost completely suppressed by the inactivation of MSH2 [25].
• In contrast to their similar antimutator roles, Pms1p consistently inhibited recombination to a lesser degree than did Msh2p [26].

Other interactions of MSH2

• Of these, MLH1 and PMS1 are known to act in the MSH2-dependent pathway that repairs DNA mismatches [27].
• 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 [28].
• Using a chromosomally integrated inverted-repeat substrate, we also show that loss of both pso2 and exo1/msh2 reduces spontaneous homologous recombination rates [29].
• The pol30-201 mutation altered an amino acid (C22Y) located on the surface of the PCNA trimer that slides over the DNA but did not cause a defect in MSH2-MSH6 binding in vitro [28].
• These results indicate that MSH1 plays a role in repair or stability of mtDNA and MSH2 plays a role in repair of 4-bp insertion/deletion mispairs in the nucleus [1].

Analytical, diagnostic and therapeutic context of MSH2

• Two different aa replacements which correspond to previously observed sequence variants of the human MSH2 gene, and implicated in HNPCC, were created in the conserved aa of the yeast MSH2 gene by site directed mutagenesis [30].
• In this study, the S. cerevisiae 109-kDa Msh2 and 140-kDa Msh6 proteins were cooverexpressed in S. cerevisiae and shown to interact in an immunoprecipitation assay and by conventional chromatography [31].
• The interaction of the Saccharomyces cerevisiae MSH2-MSH6 complex with mispaired bases was analyzed using gel mobility shift assays and surface plasmon resonance methods [32].
• We investigated yeast Msh2p association with recombination intermediates in vivo using chromatin immunoprecipitation [33].
• In msh2 mutants lacking the long-patch repair system, sequence analysis of recombination tracts resulting from exchanges between similar but non-identical (homeologous) parental DNAs showed the occurrence of short-patch repair events that can involve <12 nucleotides [34].

References