Separation-of-function mutations in Saccharomyces cerevisiae MSH2 that confer mismatch repair defects but do not affect nonhomologous-tail removal during recombination

Yeast Msh2p forms complexes with Msh3p and Msh6p to repair DNA mispairs tha t arise during DNA replication. In addition to their role in mismatch repai r (MMR), the MSH2 and MSH3 gene products are required to remove 3' nonhomol ogous DNA tails during genetic recombination. The mismatch repair genes MSH 6, MLH1, and PMS1, whose products interact with Msh2p, are not required in this process. We have identified mutations in MSH2 that do not disrupt gene tic recombination but confer a strong defect in mismatch repair. Twenty-fou r msh2 mutations that conferred a dominant negative phenotype for mismatch repair were isolated. A subset of these mutations mapped to residues in Msh 2p that were analogous to mutations identified in human nonpolyposis colore ctal cancer msh2 kindreds. Approximately half of the these MMR-defective mu tations retained wild-type or nearly wild-type activity for the removal of nonhomologous DNA tails during genetic recombination. The identification of mutations in MSH2 that disrupt mismatch repair without affecting recombina tion provides a first step in dissecting the Msh-effector protein complexes that are thought to play different roles during DNA repair and genetic rec ombination.