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MSH6, a Saccharomyces cerevisiae protein that binds to mismatches as a heterodimer with MSH2
I Iaccarino1, F Palombo, J Drummond
1Istituto de Richerche di Biologia Molecolare P. Angeletti, Pomezia, Italy.
Abstract:
The process of post-replicative DNA-mismatch repair seems to be highly evolutionarily conserved. In Escherichia coli, DNA mismatches are recognized by the MutS protein. Homologues of the E. coli mutS and mutL mismatch-repair genes have been identified in other prokaryotes, as well as in yeast and mammals. Recombinant Saccharomyces cerevisiae MSH2 (MSH for MutS homologue) and human hMSH2 proteins have been shown to bind to mismatch-containing DNA in vitro. However, the physiological role of hMSH2 is unclear, as shown by the recent finding that the mismatch-binding factor hMutS alpha isolated from extracts of human cells is a heterodimer of hMSH2 and another member of the MSH family, GTBP. It has been reported that S. cerevisiae possesses a mismatch-binding activity, which most probably contains MSH2. We show here that, as in human cells, the S. cerevisiae binding factor is composed of MSH2 and a new functional MutS homologue, MSH6, identified by its homology to GTBP.
Insights
DNA mismatch repair is conserved across species. In yeast, the MSH2 protein, along with a newly identified MutS homologue MSH6, forms the primary DNA mismatch binding factor, similar to human cells.
Area of Science:
- Molecular Biology
- Genetics
- Evolutionary Biology
Background:
- Post-replicative DNA mismatch repair is an evolutionarily conserved process crucial for maintaining genomic integrity.
- In Escherichia coli, the MutS protein initiates DNA mismatch recognition.
- Homologues of E. coli mutS and mutL genes are found in prokaryotes, yeast, and mammals, indicating functional conservation.
Purpose of the Study:
- To investigate the composition and function of the DNA mismatch binding factor in Saccharomyces cerevisiae.
- To determine if yeast possesses a similar mismatch repair complex to that found in human cells.
Main Methods:
- Identification and characterization of MutS homologues in Saccharomyces cerevisiae.
- Biochemical analysis of DNA mismatch binding activity in yeast extracts.
- Comparison of yeast mismatch binding factors with human hMutS alpha.
Main Results:
- The DNA mismatch binding factor in Saccharomyces cerevisiae is a heterodimer composed of MSH2 and a novel MutS homologue, MSH6.
- MSH6 is identified as a functional homologue of GTBP, a component of the human mismatch binding factor.
- This finding suggests a conserved mechanism for DNA mismatch recognition in yeast and humans.
Conclusions:
- The DNA mismatch repair system in yeast, involving MSH2 and MSH6, is functionally analogous to the human system.
- The identification of MSH6 highlights the evolutionary conservation of key components in DNA mismatch repair pathways.
- This study provides critical insights into the molecular mechanisms underlying genome stability in eukaryotes.