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XULAneXUS

Publication Date

6-15-2024

Abstract

Defects in the DNA mismatch repair process results in the accumulation of mutations and disease. Mutations in MSH6 and MSH2, encoding for the subunits of the MutSα complex, are often responsible for Constitutional Mismatch Repair Deficiency (CMMRD) and Lynch Syndrome (LS), respectively. This work focused on DNA mismatch repair through analysis of the MSH6 missense variant msh6-K336T. The mutation examined in this study is msh6-K336T in Saccharomyces cerevisiae, which is equivalent to msh6-K431T in humans. The mutation results in the replacement of lysine with threonine, an amino acid with different properties. It was therefore hypothesized that the mutation would prevent MutSα complex interaction, effectively hindering recognition and subsequent repair of mismatches. Based on Sorting Intolerant from Tolerant (SIFT) Analysis, it was predicted that the amino acid change will be tolerated in humans and not tolerated in yeast. Combination of Different Properties of Msh6 Protein (CoDP) Analysis predicted that the mutation would likely impair molecular function. Investigation of msh6-K336T was carried out by transforming a plasmid containing the msh6-K336T into yeast lacking the MSH6 gene. Diploid cells containing the msh6-K336T and a wild-type copy of the MSH6 gene were also analyzed. The responses to the CAN1 forward mutation assay were examined to understand the severity of the mutation in MMR. It was determined that msh6-K336T yeast strains behaved very similarly to wild-type strains in the assay, indicating this allele displays a wild-type phenotype and is not defective in the DNA MMR process.

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