General Information about MutS proteins

The ability of many species to repair mismatches in double-stranded DNA has been well documented. The first critical step in this process is the recognition of the mismatched DNA. In the major mismatch repair pathway in Escherichia coli, this is accomplished by the MutS protein. The MutS protein binds to the site of a mismatch in double-stranded DNA and, with the cooperation of the MutL and MutH proteins, targets a section of one of the DNA strands at that location for removal. Other proteins complete the repair process: the section of DNA that has been targeted is removed and degraded, a patch is synthesized using the complementary strand as a template, and the patch is ligated into place resulting in a repaired section of double-stranded DNA without mismatches.

As might be expected, since mismatches can arise in a variety of circumstances, the proteins involved in mismatch repair have multiple cellular roles. These include the limitation of mutations due to misincorporation and strand-slippage during DNA replication, the regulation of interspecies recombination (since recombination between non-identical DNA sequences can result in mismatches) and the repair of certain types of DNA damage.

Much interest has focused on the human MutS homologs since defects in some of these are responsible for some forms of hereditary non-polyposis colon cancer (HNPCC) and possibly some spontaneous cancers.

The comparison between eukaryotes and bacteria is complicated by the fact that eukaryotes encode multiple MutS homologs. For example, in yeast there are six MutS homologs, MSH 1-6. Two of these (MSH4 and MSH5) do not even function in mismatch repair but instead are involved in meiotic crossing-over and chromosome segregation. The other four have roles in mismatch repair but these roles are not completely overlapping. MSH2, MSH3, and MSH6 are involved in the repair of mismatches in nuclear DNA. MSH2 is required for all such repair and MSH3 and MSH6 provide specificity for the type of mismatch: MSH6 for base:base mismatches and small loops and MSH3 for large loops. The function of MSH1 is not well characterized but it appears to be involved in repair of mismatches in mitochondrial DNA. Many other eukaryotic species been found to encode multiple MutS homologs. The functions of some of these forms are known, and many show clear homology at the sequence and functional level to the yeast proteins.

Multiple MutS homologs have recently been found in many bacterial species including Bacillus subtilis and the cyanobacterium Synechocystis sp. PCC6803. However, it is not known whether the roles of the two MutS-like proteins in any of these bacteria are distinct.