HMUTS-BETA, A HETERODIMER OF HMSH2 AND HMSH3, BINDS TO INSERTION DELETION LEAPS IN DNA/

In human cells, mismatch recognition is mediated by a heterodimeric co mplex, hMutS alpha, comprised of two members of the MutS homolog (MSH) family of proteins, hMSH2 and GTBP [1,2]. Correspondingly, tumour-der ived cell lines defective in hMSH2 and GTBP have a mutator phenotype [ 3,4], and extracts prepared from these cells lack mismatch-binding act ivity [1]. However, although hMSH2 mutant cell lines showed considerab le microsatellite instability in tracts of mononucleotide and dinucleo tide repeats [4,5], only mononucleotide repeats were somewhat unstable In GTBP mutants [4,6]. These findings, together with data showing tha t extracts of cells lacking GTBP are partially proficient in the repai r of two-nucleotide loops [2], suggested that loop repair can be GTBP- independent. We show here that hMSH2 can also heterodimerize with a th ird human MSH family member, hMSH3, and that this complex, hMutS beta, binds loops of one to four extrahelical bases. Our data further sugge st 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].