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J. Biol. Chem., Vol. 282, Issue 7, 5063-5074, February 16, 2007

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The Central Role of PDR1 in the Foundation of Yeast Drug Resistance^*

Vivienne Fardeau¹, Gaëlle Lelandais², Andrew Oldfield, Hélène Salin³, Sophie Lemoine, Mathilde Garcia¹, Véronique Tanty, Stéphane Le Crom^¶, Claude Jacq, and Frédéric Devaux⁴

From the Laboratoire de Génétique Moléculaire, CNRS UMR8541, the ^¶Laboratoire de Biologie Moléculaire du Développement, INSERM U368, and the Plate-forme Transcriptome IFR36, Ecole Normale Supérieure, 75230 Paris cedex 05, France

The widespread pleiotropic drug resistance (PDR) phenomenon is well described as the long term selection of genetic variants expressing constitutively high levels of membrane transporters involved in drug efflux. However, the transcriptional cascades leading to the PDR phenotype in wild-type cells are largely unknown, and the first steps of this phenomenon are poorly understood. We investigated the transcriptional mechanisms underlying the establishment of an efficient PDR response in budding yeast. We show that within a few minutes of drug sensing yeast elicits an effective PDR response, involving tens of PDR genes. This early PDR response (ePDR) is highly dependent on the Pdr1p transcription factor, which is also one of the major genetic determinants of long term PDR acquisition. The activity of Pdr1p in early drug response is not drug-specific, as two chemically unrelated drugs, benomyl and fluphenazine, elicit identical, Pdr1p-dependent, ePDR patterns. Our data also demonstrate that Pdr1p is an original stress response factor, the DNA binding properties of which do not depend on the presence of drugs. Thus, Pdr1p is a promoter-resident regulator involved in both basal expression and rapid drug-dependent induction of PDR genes.

Received for publication, October 31, 2006 , and in revised form, December 7, 2006.

^* This work was supported in part by grants from ARC (ARC3310) and CNRS (ACI IMPBIO 2004-45). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1, S2, and S4 and Figs. S3 and S5.

¹ Recipients of Ph.D. grants from the MENRT.

² Present address: Equipe de Bioinformatique Génomique et Moléculaire, INSERM U726, Université Paris 7, 2 place Jussieu 75251 Paris cedex 05.

³ Recipient of a CNRS postdoctoral fellowship in the framework of the national Toxicologie Nucléaire program.

⁴ To whom correspondence should be addressed: Laboratoire de Génétique Moléculaire, CNRS UMR8541, Ecole Normale Supérieure, 75230 Paris cedex 05 France. Tel.: 33-1-44-32-35-72; Fax: 33-1-44-32-39-41; E-mail: devaux{at}biologie.ens.Fr.

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