Zinc cluster protein Rdr1p is a transcriptional repressor of the PDR5 gene encoding a multidrug transporter.
The yeast PDR5 gene encodes an efflux pump that confers multidrug resistance. Expression of PDR5 is positively regulated by the transcription factors Pdr1p and Pdr3p that recognize the same pleiotropic drug resistance elements (PDREs) in the PDR5 promoter. Pdr1p and Pdr3p belong to the Gal4p family of zinc cluster proteins. The function of RDR1 (YOR380W), which also encodes a member of this family, is unknown. To identify target genes for Rdr1p, we have performed whole-genome analysis of gene expression with DNA microarrays. Our results show that Rdr1p is a transcriptional repressor of five genes, including PDR5. A Deltardr1 strain has increased resistance to cycloheximide, as expected from the overexpression of PDR5. In addition, the activity of a PDR5-lacZ reporter is increased in a Deltardr1 strain. All (but one) genes affected by removal of Rdr1p contain PDREs in their promoters. We tested if the effect of Rdr1p is mediated through PDREs by inserting this DNA element in front of a minimal promoter. Activity of this reporter was increased in a Deltardr1 strain. Moreover, mutations known to reduce binding of Pdr1/Pdr3p abolished the induction observed in the Deltardr1 strain. Thus, we have identified a transcriptional repressor involved in the control of multidrug resistance.
Hellauer
Karen
K
Department of Medicine, McGill University Health Centre, Royal Victoria Hospital, McGill University, Montréal, Québec H3A 1A1, Canada.
Akache
Bassel
B
MacPherson
Sarah
S
Sirard
Edith
E
Turcotte
Bernard
B
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000302:isolation & purification* / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000302:isolation & purification / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C089261:PDR3 protein, S cerevisiae; C092438:PDR5 protein, S cerevisiae; C459602:RDR1 protein, S cerevisiae; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D003513:Cycloheximide