hMutSbeta, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNA

In human cells, mismatch recognition is mediated by a heterodimeric complex, hMutSalpha, comprised of two members of the MutS homolog (MSH) family of proteins, hMSH2 and GTBP [1,2]. Correspondingly, tumour-derived cell lines defective in hMSH2 and GTBP have a mutator phenotype [3,4], and extracts prepared from these cells lack mismatch-binding activity [1]. However, although hMSH2 mutant cell lines showed considerable microsatellite instability in tracts of mononucleotide and dinucleotide repeats [4,5], only mononucleotide repeats were somewhat unstable in GTBP mutants [4,6]. These findings, together with data showing that extracts of cells lacking GTBP are partially proficient in the repair of two-nucleotide loops [2], suggested that loop repair can be GTBP-independent. We show here that hMSH2 can also heterodimerize with a third human MSH family member, hMSH3, and that this complex, hMutSbeta, binds loops of one to four extrahelical bases. Our data further suggest that hMSH3 and GTBP are redundant in loop repair, and help explain why only mutations in hMSH2, and not in GTBP or hMSH3, segregate with hereditary non-polyposis colorectal cancer (HNPCC) [7].