Disease relevance of MSH3

• Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair [1].
• Serum mannan-binding protein (MBP), a lectin specific for mannose and N-acetylglucosamine, was revealed to activate the complement system as measured by passive hemolysis using sheep erythrocytes coated with yeast mannan [2].
• The MBP-Rok1 hybrid protein was synthesized in Escherichia coli and purified by amylose affinity column and ion exchange chromatography [3].
• Because of the inflammatory nature of pancreatitis, we postulate that the pancreas produces endogenous MBP [4].

High impact information on MSH3

• In yeast, mutations in several genes, including RTH and MSH3, cause microsatellite instability [1].
• Introducing chromosome 5, encoding the MSH3 gene, into the mutant cell line increased the stability of some but not all microsatellites [1].
• Together the data suggest that the MSH3 gene encodes a product that functions in repair of some but not all pre-mutational intermediates, its mutation in tumours can result in genomic instability and, as in yeast, MSH3 and MSH6 are partially redundant for mismatch repair [1].
• Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair [5].
• These findings argue that Msh2p-Msh3p associates with intermediates early in DSBR to participate in the rejection of homeologous pairing and to stabilize nonhomologous tails for cleavage by Rad1p-Rad10p endonuclease [6].

Biological context of MSH3

• In addition to their role in mismatch repair (MMR), the MSH2 and MSH3 gene products are required to remove 3' nonhomologous DNA tails during genetic recombination [7].
• Interestingly, MSH3 (and thus MutSbeta) is missing in some genomes, as for example in Drosophila, or is present as in Schizosaccharomyces pombe but appears to play no role in MMR [8].
• In contrast, transcription of the MSH1, MSH3 and MLH1 genes was not regulated during the cell cycle [9].
• Yeast Msh2p forms complexes with Msh3p and Msh6p to repair DNA mispairs that arise during DNA replication [7].
• We find that a mutation in the yeast gene MSH3 that does not substantially affect the rate of spontaneous mutations at several loci increases microsatellite instability about 40-fold, preferentially causing deletions [10].

Anatomical context of MSH3

• In contrast, expression of Msh3 was at its highest level in pachytene spermatocytes [11].
• To determine the role of MSH3 in mammalian mismatch repair, we employed MSH3-deficient Chinese hamster ovary (CHO) cell lines [12].
• F19 was either expressed as a fusion with the maltose binding protein (MBP) or directly addressed to the periplasm by fusing it with the MBP signal peptide [13].
• CONCLUSION: We isolated an MBP from the pancreas and identified it as pancreatic elastase [4].
• Inhibition of phagocytosis of the yeast also resulted from pretreatment of either the macrophages or the yeasts with MBP followed by washing [14].

Associations of MSH3 with chemical compounds

• Yeast strains containing alanine substitutions in the PCNA binding motif of Msh6 or Msh3 had elevated mutation rates, indicating that these interactions are important for genome stability [15].
• 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].
• The human mannose-binding protein (MBP) is a multimeric serum protein that is divided into three domains: a cysteine-rich NH2-terminal domain that stabilizes the alpha-helix of the second collagen-like domain, and a third COOH-terminal carbohydrate binding region [17].
• The activation by serum MBP was inhibited effectively by the presence of haptenic sugars and dependent absolutely upon the presence of C4, indicating that the activation is initiated by the sugar binding activity of MBP and proceeds through the classical pathway [2].
• Preincubation of yeasts with rabbit mannose-binding protein (MBP) resulted in dose-related enhancement of TNF-alpha secretion, through a Ca++-dependent pathway inhibited by D-mannose [18].

Other interactions of MSH3

• The mismatch repair mutations pms1, msh2 and msh3 did not affect 31- and 61-bp deletions in the pol3-t but increased the rates of 7- and 1-bp deletions [19].
• The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations [20].
• Among the genes involved in this suppression were three genes involved in mismatch repair--MSH2, MSH3, and MSH6--and one in nucleotide excision repair, RAD1 [21].

Analytical, diagnostic and therapeutic context of MSH3

• The median MBP level of ten children previously shown to have the functional opsonic defect was 4.9 micrograms/l (range 2.5-35.0 micrograms/l) compared with 143 micrograms/l (range 2.5-880 micrograms/l) for a paediatric control group [22].
• We also demonstrate that Kcc4 associates with septin proteins in vitro and in vivo by two-hybrid analysis, GST pull-down experiments, immunoprecipitation, and analysis of direct association with affinity-purified GST-Kcc4 and MBP-Septin proteins [23].
• In this publication we describe that maltose binding protein (MBP) fused to the C-terminus of the plant photoreceptor phytochrome B allows purification of the fusion protein via amylose affinity chromatography [24].

References