Cross-talk between transcriptional regulators of multidrug resistance in Saccharomyces cerevisiae

Multiple or pleiotropic drug resistance often arises in the yeast Saccharom yces cerevisiae due to genetic alterations of the functional state of the C ys(6)-Zn(II)(2) transcription factors Pdr1p and Pdr3p, Single amino acid su bstitutions give rise to hyperactive forms of these regulatory proteins, wh ich in turn cause overproduction of downstream target genes that directly m ediate multidrug resistance. Previous work has identified a novel Cys(6)-Zn (II)(2) transcription factor designated Yrr1p as mutant forms of this prote in confer high level resistance to the cell cycle inhibitor reveromycin A a nd DNA damaging agent 4-nitroquinoline-N-oxide. In the present study, we de monstrate that Yrr1p also mediates oligomycin resistance through activation of the ATP-binding cassette transporter-encoding gene YOR1, Additionally, insertion of triplicated copies of the hemagglutinin epitope in the C-termi nal region of Yrr1p causes the protein to behave as a hyperactive regulator of transcription. We have found that YRR1 expression is both controlled in a. Pdr1p/Pdr3p-dependent- manner and autoregulated. Chromatin immunoprecip itation experiments also show that Yrr1p associates with target prometers i n vivo, Together these data argue that the signal generated by activation o f Pdr1p and/or Pdr3p can be amplified through the action of these transcrip tional regulatory proteins on downstream target genes, like YRR1, that also encode transcription factors.