MutSα MutSβ, MutLα and DNA polymerase ôin human mismatch repair

The human mismatch repair system corrects the eight hase-hase mismatches and insertion/deletion loops of 1-10 nucleotides. Using an in vitro assay, we have screened extracts from twenty-two cell lines derived from sporadic and hereditary RER (replication error prone) cancers of colorectal. endometrial, ovarian and lymphoid origin. Twenty-one of these were found to be deficient in mismatch repair, with the deficiency in each case atlrihutahle to molecular defects m MutSa (a heterodimer of MSH2 and MSH6i or MutLa (a heterodimer ot MLH1 and PMS2), suggesting that defects in either of these activities account for the vast majority of RER+ tumors In addition to MutSa and MutLa, recent work has implicated two additional activities in human mismatch repair: DNA polymerase ôand MutSβ (a heterodimer of MSH2 and MSH3). In contrast to MutSa.which is required for hase-hase mismatch repair and plays a role in correction of insertion/deletion heterologies, MutSβ contributes only to correction of the latter class of mispairs. The majority of nuclear MSH2 is eomplexed with MSH6 in the form of MutSa. with a minor fraction present in the MutSβ complex with MSH3. In addition to its ability to recognize mismatches, MutSa recognises the cytotoxic lesions produced by DNA methylating agents and cisplatin. Collaborative experiments with William Thilly (M.I.T.) and Robert Brown (CRC Beatson Laboratories) have demonstrated that cell lines deficient in MutSa or MutLa are resistant to the cytotoxic effects of these agents.