Nonidentical function of Upc2A binding sites in the Candida glabrata CDR1 promoter

Bao Gia Vu; William Scott Moye-Rowley

doi:10.1093/genetics/iyac135

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Nonidentical function of Upc2A binding sites in the Candida glabrata CDR1 promoter

Journal article

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Peer reviewed

Nonidentical function of Upc2A binding sites in the Candida glabrata CDR1 promoter

Bao Gia Vu and William Scott Moye-Rowley

Genetics (Austin), Vol.222(2), iyac135

09/30/2022

DOI: 10.1093/genetics/iyac135

PMCID: PMC9526049

PMID: 36063046

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9526049View

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Abstract

Increased expression of the Candida glabrata CDR1 gene, encoding an ATP-binding cassette membrane transporter, is routinely observed in fluconazole-resistant isolates of this pathogenic yeast. CDR1 transcription has been well-documented to be due to activity of the Zn2Cys6 zinc cluster-containing transcription factor Pdr1. Gain-of-function mutations in the gene encoding this factor are the most commonly observed cause of fluconazole hyper-resistance in clinical isolates. We have recently found that the sterol-responsive transcription factor Upc2A also acts to control CDR1 transcription, providing a direct link between ergosterol biosynthesis and expression of Pdr1 target genes. While this earlier work implicated Upc2A as an activator of CDR1 transcription, our further analyses revealed the presence of a second Upc2A binding site that negatively regulated CDR1 expression. This Upc2A binding site designated a sterol-responsive element (SRE) was found to have significant lower affinity for Upc2A DNA-binding than the previously described SRE. This new SRE was designated SRE2 while the original, positively acting site was named SRE1. A mutant version of SRE2 prevented in vitro DNA-binding by recombinant Upc2A and, when introduced into the CDR1 promoter, caused decreased fluconazole susceptibility and increased CDR1 expression. This negative effect caused by loss of SRE2 was shown to be Pdr1 independent, consistent with the presence of at least one additional activator of CDR1 transcription. The ability of Upc2A to exert either positive or negative effects on gene expression resembles behavior of mammalian nuclear receptor proteins and reveals an unexpectedly complex nature for SRE effects on gene regulation.

Zinc

Adenosine Triphosphate - metabolism

Antifungal Agents - pharmacology

ATP-Binding Cassette Transporters - genetics

ATP-Binding Cassette Transporters - metabolism

Binding Sites

Candida albicans - genetics

Candida glabrata - genetics

DNA - metabolism

Drug Resistance, Fungal - genetics

Ergosterol

Fluconazole - pharmacology

Fungal Proteins - genetics

Fungal Proteins - metabolism

Gene Expression Regulation, Fungal

Sterols - metabolism

Transcription Factors - genetics

Transcription Factors - metabolism

Details

Title: Subtitle: Nonidentical function of Upc2A binding sites in the Candida glabrata CDR1 promoter
Creators: Bao Gia Vu - Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
William Scott Moye-Rowley - University of Iowa, Molecular Physiology and Biophysics
Resource Type: Journal article
Publication Details: Genetics (Austin), Vol.222(2), iyac135
DOI: 10.1093/genetics/iyac135
PMID: 36063046
PMCID: PMC9526049
NLM abbreviation: Genetics
ISSN: 0016-6731
eISSN: 1943-2631
Grant note: R01 AI152494 / NIAID NIH HHS
Language: English
Date published: 09/30/2022
Academic Unit: Molecular Physiology and Biophysics
Record Identifier: 9984460056402771

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