We use yeast and mice to study DNA mismatch repair (MMR), which corrects mismatches and senses DNA damage. MMR gene mutations increase spontaneous mutation and predispose to hereditary and sporadic cancer.  Using gene targeting strategies, we derive and study knockout mice for four MutL homologs, Mlh1, Pms1 or Pms2, and Mlh3. We have observed increased mutation and cancer risk in these animals, although the severity varies between the different knockouts. In a related project, we have developed an assay using the site-specific recombinase Cre to stochastically inactivate tumor suppressor genes or activate oncogenes in the mouse. The system also uses a color marker (B-galactosidase) which is activated by the recombinase thus marking those cell lineages experiencing inactivation (or activation) of the "loxp"-tagged tumor suppressors/oncogenes. One question being addressed is "What is the minimum number of cancer gene alterations that are sufficient to promote intestinal tumor formation and progression in the mouse?" Our studies in yeast are centered on a better understanding of the mechanism and gene products involved in DNA mismatch repair.