An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1

Selmecki, Anna; Gerami‐Nejad, Maryam; Paulson, Carsten; Forche, Anja; Berman, Judith

doi:10.1111/j.1365-2958.2008.06176.x

Cited by 325Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1

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Selmecki, Anna, Gerami‐Nejad, Maryam, Paulson, Carsten, Forche, Anja, Berman, Judith·2008·Molecular Microbiology

DOI 10.1111/j.1365-2958.2008.06176.x

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Abstract

Acquired azole resistance is a serious clinical problem that is often associated with the appearance of aneuploidy and, in particular, with the formation of an isochromosome [i(5L)] in the fungal opportunist Candida albicans. Here we exploited a series of isolates from an individual patient during the rapid acquisition of fluconazole resistance (Flu(R)). Comparative genome hybridization arrays revealed that the presence of two extra copies of Chr5L, on the isochromosome, conferred increased Flu(R) and that partial truncation of Chr5L reduced Flu(R). In vitro analysis of the strains by telomere-mediated truncations and by gene deletion assessed the contribution of all Chr5L genes and of four specific genes. Importantly, ERG11 (encoding the drug target) and a hyperactive allele of TAC1 (encoding a transcriptional regulator of drug efflux pumps) made independent, additive contributions to Flu(R) in a gene copy number-dependent manner that was not different from the contributions of the entire Chr5L arm. Thus, the major mechanism by which i(5L) formation causes increased azole resistance is by amplifying two genes: ERG11 and TAC1.

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Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation.
“Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation.”
From The evolution of drug resistance in clinical isolates of Candida albicans. (2015) · cites this paper as Selmecki et al., 2008
The i5(L) aneuploidy results in increased dosage of genes encoding both the azole target Erg11 and the transcription factor regulating drug efflux, Tac1.
“This aneuploidy results in increased dosage of genes encoding both the azole target Erg11 and the transcription factor regulating drug efflux, Tac163.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [63]
i(5L) can arise rapidly under fluconazole selection, occurs in diverse genetic backgrounds of Candida albicans, and frequently results in multi-azole resistance.
“i(5L) can arise rapidly under FLC selection, occurs in diverse genetic backgrounds of C. albicans, and frequently results in multi-azole resistance (Selmecki et al. 2008, 2009).”
From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans (2023) · cites this paper as Selmecki et al. 2008
Isochromosome 5L (i(5L)) causes drug resistance via an increase in the copy number of ERG11 and TAC1.
“One specific segmental aneuploidy, isochromosome 5L (i(5L)), causes drug resistance via an increase in the copy number of ERG11 and TAC1 (Selmecki et al. 2006, 2008).”
From Antifungal Drug Concentration Impacts the Spectrum of Adaptive Mutations in Candida albicans (2023) · cites this paper as Selmecki et al. 2008
The isochromosome 5L region carries the ERG11 and TAC1 genes involved, respectively, in ergosterol synthesis and drug efflux.
“This region carries the ERG11 and TAC1 genes involved, respectively, in ergosterol synthesis and drug efflux [127].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [127]

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Authors: Selmecki, A., Gerami‐Nejad, M., Paulson, C., Forche, A., & Berman, J.
Affiliations: University of Minnesota (US)
Corresponding author: Berman, Judith
ORCID: Selmecki, Anna
Forche, Anja
Berman, Judith
Venue: Molecular Microbiology
Publisher: Wiley
Published: 2008-03-20
Volume: 68
Issue: 3
Pages: 624-641
ISSN: 0950-382X (ISSN-L)
1365-2958
DOI: 10.1111/j.1365-2958.2008.06176.x
OpenAlex: W2145329735
Cited by: 325
References: 56
Citations by year: 2026: 15 · 2025: 19 · 2024: 28 · 2023: 17 · 2022: 19 · 2021: 22 · 2020: 14 · 2019: 26 · 2018: 16 · 2017: 18 · 2016: 10 · 2015: 16 · 2014: 22 · 2013: 16 · 2012: 23
FWCI: 9.48
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Molecular Microbiology (publishedVersion)
PubMed (publishedVersion)
Bowdoin - Digital Commons (Bowdoin College) (submittedVersion)
Funders: National Institutes of Health
National Institute of Allergy and Infectious Diseases (R01AI062427)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords: Candida albicans, fluconazole resistance, azole resistance, ERG11, TAC1, gene amplification, drug efflux pumps, transcription factors, gene copy number, aneuploidy, gene deletion
MeSH terms: Antifungal Agents, Candida albicans, Candidiasis, Fungal Proteins, Gene Amplification, Humans, Microbial Sensitivity Tests, Polymorphism, Restriction Fragment Length, Fluconazole, Chromosomes, Fungal, Open Reading Frames, Gene Deletion, Isochromosomes, Gene Dosage, Polymorphism, Single Nucleotide, Drug Resistance, Fungal

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An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1

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