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J. Biol. Chem., Vol. 279, Issue 41, 42677-42686, October 8, 2004

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On the Mechanism of Constitutive Pdr1 Activator-mediated PDR5 Transcription in Saccharomyces cerevisiae

EVIDENCE FOR ENHANCED RECRUITMENT OF COACTIVATORS AND ALTERED NUCLEOSOME STRUCTURES^*

Chen Gao, Luming Wang, Elena Milgrom, and W.-C. Winston Shen

From the Department of Biochemistry and Molecular Biology, State University of New York Upstate Medical University, Syracuse, New York 13210

Drug resistance as a result of overexpression of drug transporter genes presents a major obstacle in the treatment of cancers and infections. The molecular mechanisms underlying transcriptional up-regulation of drug transporter genes remains elusive. Employing Saccharomyces cerevisiae as a model, we analyzed here transcriptional regulation of the drug transporter gene PDR5 in a drug-resistant pdr1-3 strain. This mutant bears a gain-of-function mutation in PDR1, which encodes a transcriptional activator for PDR5. Similar to the well studied model gene GAL1, we provide evidence showing that PDR5 belongs to a group of genes whose transcription requires the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex. We also show that the drugindependent PDR5 transcription is associated with enhanced promoter occupancy of coactivator complexes, including SAGA, Mediator, chromatin remodeling SWI/SNF complex, and TATA-binding protein. Analyzed by chromatin immunoprecipitations, loss of contacts between histones and DNA occurs at both promoter and coding sequences of PDR5. Consistently, micrococcal nuclease susceptibility analysis revealed altered chromatin structure at the promoter and coding sequences of PDR5. Our data provide molecular description of the changes associated with constitutive PDR5 transcription, and reveal the molecular mechanism underlying drug-independent transcriptional up-regulation of PDR5.

Received for publication, June 8, 2004 , and in revised form, August 4, 2004.

^* This work was supported by the Faculty Development Fund from the Department of Biochemistry and Molecular Biochemistry, SUNY Upstate Medical University. 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.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, 750 East Adams St., Rm. 4281 WHA, Syracuse, NY 13210. Tel.: 315-464-8751; Fax: 315-464-8750; E-mail: shenw{at}upstate.edu.

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