Positive autoregulation and repression of transactivation are key regulatory features of the Candida glabrata Pdr1 transcription factor

Svetlana Khakhina; Lucia Simonicova; W Scott Moye-Rowley

doi:10.1111/mmi.13913

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Positive autoregulation and repression of transactivation are key regulatory features of the Candida glabrata Pdr1 transcription factor

Journal article

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Positive autoregulation and repression of transactivation are key regulatory features of the Candida glabrata Pdr1 transcription factor

Svetlana Khakhina, Lucia Simonicova and W Scott Moye-Rowley

Molecular microbiology, Vol.107(6), pp.747-764

03/2018

DOI: 10.1111/mmi.13913

PMCID: PMC5842128

PMID: 29363861

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Abstract

Resistance to azole drugs, the major clinical antifungal compounds, is most commonly due to gain-of-function (GOF) substitution mutations in a gene called PDR1 in the fungal pathogen Candida glabrata. PDR1 encodes a zinc cluster-containing transcription factor. GOF forms of Pdr1 drive high level expression of downstream target gene expression with accompanying azole resistance. PDR1 has two homologous genes in Saccharomyces cerevisiae, called ScPDR1 and ScPDR3. This study provides evidence that the PDR1 gene in C. glabrata represents a blend of the properties found in the two S. cerevisiae genes. We demonstrated that GOF Pdr1 derivatives are overproduced at the protein level and less stable than the wild-type protein. Overproduction of wild-type Pdr1 increased target gene expression but to a lesser extent than GOF derivatives. Site-directed mutagenesis of Pdr1 binding sites in the PDR1 promoter provided clear demonstration that autoregulation of PDR1 is required for its normal function. An internal deletion mutant of Pdr1 lacking its central regulatory domain behaved as a hyperactive transcription factor that was lethal unless conditionally expressed. A full understanding of the regulation of Pdr1 will provide a new avenue of interfering with azole resistance in C. glabrata.

Antifungal Agents - pharmacology

ATP-Binding Cassette Transporters - metabolism

Binding Sites

Candida glabrata - genetics

Candida glabrata - metabolism

DNA-Binding Proteins - genetics

DNA-Binding Proteins - metabolism

Drug Resistance, Fungal

Fluconazole - pharmacology

Gene Expression Regulation, Fungal - drug effects

Promoter Regions, Genetic

Saccharomyces cerevisiae - genetics

Saccharomyces cerevisiae Proteins - genetics

Saccharomyces cerevisiae Proteins - metabolism

Trans-Activators - metabolism

Transcription Factors - genetics

Transcription Factors - metabolism

Transcriptional Activation - drug effects

Details

Title: Subtitle: Positive autoregulation and repression of transactivation are key regulatory features of the Candida glabrata Pdr1 transcription factor
Creators: Svetlana Khakhina - Roy J. and Lucille A. Carver College of Medicine
Lucia Simonicova - University of Iowa
W Scott Moye-Rowley - Roy J. and Lucille A. Carver College of Medicine
Resource Type: Journal article
Publication Details: Molecular microbiology, Vol.107(6), pp.747-764
DOI: 10.1111/mmi.13913
PMID: 29363861
PMCID: PMC5842128
NLM abbreviation: Mol Microbiol
ISSN: 0950-382X
eISSN: 1365-2958
Grant note: R01 GM049825 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 03/2018
Academic Unit: Molecular Physiology and Biophysics; Internal Medicine
Record Identifier: 9984297611302771

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