Identification of hMutLβ, a heterodimer of hMLH1 and hPMS1

hMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutL alpha. Tumors or cell Lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 and hPMS2 genes predispose to hereditary non-polyposis colon cancer, A third MutL homologue, hPMS1, has also been reported to be mutated in one cancer-prone kindred, but the protein encoded by this locus has so far remained without function. We now show that hPMS1 is expressed in human cells and that it interacts with hMLH1 with high affinity to form the heterodimer hMutL beta. Recombinant hMutL alpha and hMutL beta, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. While hMutL alpha could fully complement extracts of mismatch repair-deficient cell lines lacking hMLH1 or hPMS2, hMutL beta failed to do so with any of the different substrates tested in this assay. The involvement of the latter factor in postreplicative mismatch repair thus remains to be demonstrated.