DESTABILIZATION OF TRACTS OF SIMPLE REPETITIVE DNA IN YEAST BY MUTATIONS AFFECTING DNA MISMATCH REPAIR

The genomes of all eukaryotes contain tracts of DNA in which a single base or a small number of bases is repeated. Expansions of such tracts have been associated with several human disorders including the fragi le X syndrome1. In addition, simple repeats are unstable in certain fo rms of colorectal cancer, suggesting a defect in DNA replication or re pair2-4. We show here that mutations in any three yeast genes involved in DNA mismatch repair (PMS1, MLH1 and MSH2) lead to 100- to 700-fold increases in tract instability, whereas mutations that eliminate the proof-reading function of DNA polymerases have little effect. The meio tic stability of the tracts is similar to the mitotic stability. Th re sults suggest that tract instability is associated with DNA polymerase s slipping during replication, and that some types of colorectal cance r may reflect mutations in genes involved in DNA mismatch repair.