ANALYSIS OF 2ND-SITE MUTATIONS THAT SUPPRESS THE MULTIPLE-DRUG RESISTANCE PHENOTYPE OF THE YEAST PDR1-7 ALLELE

The yeast PDR1 locus encodes a member of the C6 zinc cluster family of transciptional regulatory proteins. Among the targets of PDR1 is the yeast PDR5 locus. The product of this gene is a member of the ATP-bind ing cassette (ABC) transmembrane protein family and plays a major role in inhibitor efflux. Mutations in PDR1 affect the relative level of P DR5 transcript and can therefore result in increased or decreased drug resistance. We isolated three second-site suppressors of a PDR1-7 sem idominant hyper-resistant mutation. These mutants were drug hypersensi tive, as compared with isogenic controls. Two of the three mutations c ontained alterations in a putative DNA-binding domain. Significantly, the mutant proteins exhibited reduced DNA-binding capacity.