title: Salicylic acid resistance is conferred by a novel YRR1 mutation in Saccharomyces cerevisiae.
abstract: Yeast cells can extrude intracellular drugs through membrane-associated efflux pumps, such as ATP-binding cassette (ABC) transporters and members of the major facilitator superfamily. Gene expression of drug efflux pumps is regulated by several transcription factors involved in pleiotropic drug resistance (PDR). Salicylic acid (SA) possesses weak antifungal activity. Although the excretion mechanisms of some antifungal drugs have been revealed, the mechanism of SA extrusion remains unclear. To elucidate the mechanism of SA excretion, we screened SA-resistant mutants from random mutagenized Saccharomyces cerevisiae BY4741 cells. We successfully isolated 60 SA-resistant clones (KinSal001-060). KinSal052, one of the strongest SA-resistant clones, also exhibited resistance to 4-nitroquinoline-1-oxide and cycloheximide, indicating that it acquired the PDR phenotype. We identified a novel mutation in YRR1 conferring SA resistance to KinSal052. YRR1 encodes a Zn(II)2Cys6-type zinc-finger transcription factor that reportedly activates gene expression involved in PDR. Yeast cells carrying the yrr1 allele (yrr1-52) activated expression of several efflux pump-encoding genes, including YOR1, SNQ2, AZR1, and FLR1. These results suggested that SA resistance in KinSal052 is conferred by the overexpression of efflux pumps constitutively activated by the mutant form of Yrr1p.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Kinki University, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan. kodo@med.kindai.ac.jp
authors.forename: Naohiko
authors.initials: N
authors.lastname: Kodo
authors.forename: Toshiro
authors.initials: T
authors.lastname: Matsuda
authors.forename: Syuichi
authors.initials: S
authors.lastname: Doi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Munakata
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D026141:Drug Resistance, Multiple, Fungal / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D026901:Membrane Transport Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D027361:Organic Anion Transporters / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D020156:Salicylic Acid / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; C476997:AZR1 protein, S cerevisiae; D000935:Antifungal Agents; C118429:FLR1 protein, S cerevisiae; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; C101797:SNQ2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C097077:YOR1 protein, S cerevisiae; C481277:Yrr1 protein, S cerevisiae; D015112:4-Nitroquinoline-1-oxide; D003513:Cycloheximide; D020156:Salicylic Acid