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Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability
R E Johnson1, G K Kovvali, L Prakash
1Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, 77555-1061, USA.
Abstract:
Defects in DNA mismatch repair result in instability of simple repetitive DNA sequences and elevated levels of spontaneous mutability. The human G/T mismatch binding protein, GTBP/p160, has been suggested to have a role in the repair of base-base and single nucleotide insertion-deletion mismatches. Here we examine the role of the yeast GTBP homolog, MSH6, in mismatch repair. We show that both MSH6 and MSH3 genes are essential for normal genomic stability. Interestingly, although mutations in either MSH3 or MSH6 do not cause the extreme microsatellite instability and spontaneous mutability observed in the msh2 mutant, yeast cells harboring null mutations in both the MSH3 and MSH6 genes exhibit microsatellite instability and mutability similar to that in the msh2 mutant. Results from epistasis analyses indicate that MSH2 functions in mismatch repair in conjunction with MSH3 or MSH6 and that MSH3 and MSH6 constitute alternate pathways of MSH2-dependent mismatch repair.
Insights
Defects in DNA mismatch repair (MMR) can cause genomic instability. The yeast MSH6 gene, a homolog of human GTBP/p160, is crucial for MMR, working with MSH3 in alternate pathways.
Area of Science:
- Genetics
- Molecular Biology
- DNA Repair
Background:
- DNA mismatch repair (MMR) corrects errors during DNA replication, maintaining genomic stability.
- Defects in MMR lead to microsatellite instability and increased mutation rates.
- The human GTBP/p160 protein is implicated in repairing base-base and insertion-deletion mismatches.
Purpose of the Study:
- To investigate the role of the yeast GTBP homolog, MSH6, in DNA mismatch repair.
- To determine the functional relationship between MSH6, MSH3, and MSH2 in genomic stability.
Main Methods:
- Gene knockout studies in yeast to create msh3 and msh6 null mutants.
- Epistasis analysis to elucidate genetic interactions between MMR genes.
- Assessment of microsatellite instability and spontaneous mutability in mutant strains.
Main Results:
- Both MSH6 and MSH3 are essential for maintaining normal genomic stability in yeast.
- Msh3 and Msh6 function in parallel pathways of MSH2-dependent mismatch repair.
- Yeast strains with mutations in both MSH3 and MSH6 exhibit severe microsatellite instability and mutability, similar to msh2 mutants.
Conclusions:
- MSH6 and MSH3 are key components of distinct, yet cooperative, DNA mismatch repair pathways in yeast.
- The MSH2 protein functions with either MSH3 or MSH6 to ensure accurate DNA replication and prevent mutations.