HMSH2 FORMS SPECIFIC MISPAIR-BINDING COMPLEXES WITH HMSH3 AND HMSH6

The genetic and biochemical properties of three human MutS homologues, hMSH2, hMSH3, and hMSH6, have been examined, The full-length hMSH6 cD NA and genomic locus were isolated and characterized, and it was demon strated that the hMSH6 gene consisted of 10 exons and mapped to chromo some 2p15-16, The hMSH3 cDNA was in some cases found to contain a 27-b p deletion resulting in a loss of nine amino acids, depending on the i ndividual from which the cDNA was isolated, hMSH2, hMSH3, and hMSH6 al l showed similar tissue-specific expression patterns, hMSH2 protein fo rmed a complex with both hMSH3 and hMSH6 proteins, similar to protein complexes demonstrated by studies of the Saccharomyces cerevisiae MSH2 , MSH3, and MSH6. hMSH2 was also found to form a homomultimer complex, but neither hMSH3 nor hMSH6 appear to interact with themselves or eac h other, Analysis of the mismatched nucleotide-binding specificity of the hMSH2-hMSH3 and hMSH2-hMSN6 protein complexes showed that they hav e overlapping but not identical binding specificity, These results hel p to explain the distribution of mutations in different mismatch-repai r genes seen in hereditary nonpolyposis colon cancer.