DIAZABORINE RESISTANCE IN THE YEAST SACCHAROMYCES-CEREVISIAE REVEALS A LINK BETWEEN YAP1 AND THE PLEIOTROPIC DRUG-RESISTANCE GENES PDR1 ANDPDR3

We have investigated the mechanisms underlying resistance to the drug diazaborine in Saccharomyces cerevisiae. We used UV mutagenesis to gen erate resistant mutants, which were divided into three different compl ementation groups. The resistant phenotype in these groups was found t o be caused by allelic forms of the genes AFG2, PDR1, and PDR3. The AF G2 gene encodes an AAA (ATPases associated to a variety of cellular ac tivities) protein of unknown function, while PDR1 and PDR3 encode two transcriptional regulatory proteins involved in pleiotropic drug resis tance development. The isolated PDR1-12 and PDR3-33 alleles carry muta tions that lead to a L1044Q and a Y276H exchange, respectively. In add ition, we report that overexpression of Yap1p, the yeast homologue of the transcription factor AP1, results in a diazaborine-resistant pheno type. The YAP1-mediated diazaborine resistance is dependent on the pre sence of functional PDR1 and PDR3 genes, although PDR3 had a more pron ounced effect. These results provide the first evidence for a function al link between the Yap1p-dependent stress response pathway and Pdr1p/ Pdr3p-dependent development of pleiotropic drug resistance.