The lengths of repeated sequence segments in several human tumors have changed. Although mutations in four DNA mismatch repair genes have been linked to microsatellite instability in hereditary nonpolyposis colorectal cancer (HNPCC) families, many sporadic tumors show instability but no detectable mutations in these genes. Identifying other genes that contribute to this instability is thus of interest. Microsatellite instability is caused by mutations in various genes in yeast, including RTH and MSH3. As a result, the researchers looked for changes in FEN1 (the human homolog of RTH) and MSH3 in 16 endometrial carcinomas with microsatellite instability. Although no FEN1 mutations were detected, endometrial carcinoma and an endometrial carcinoma cell line both had a frameshift mutation in MSH3. The cell line extracts were poor in repairing mismatched or additional nucleotide-containing DNA substrates. The introduction of chromosome 5, which encodes the MSH3 gene, into the mutant cell line boosted the stability of certain microsatellites but not all. Excess nucleotide-containing substrates were repaired by extracts of these cells, but mismatches and other extra nucleotides were not repaired. A second gene mutation, a missense mutation in the MSH6 gene, was discovered in HHUA cells during a further search. The findings imply that the MSH3 gene produces a protein that acts in the repair of some but not all pre-mutational intermediates, that its mutation in tumors can cause genomic instability, and that MSH3 and MSH6 are partially redundant for mismatch repair, as in yeast.