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

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

Research output: Contribution to journalArticle

167 Citations (Scopus)

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 (FluR). Comparative genome hybridization arrays revealed that the presence of two extra copies of Chr5L, on the isochromosome, conferred increased FluR and that partial truncation of Chr5L reduced FluR. 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 FluR 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.

Original languageEnglish
Pages (from-to)624-641
Number of pages18
JournalMolecular Microbiology
Volume68
Issue number3
DOIs
StatePublished - May 2008

Fingerprint

Isochromosomes
Fluconazole
Gene Amplification
Drug Resistance
Azoles
Genes
Comparative Genomic Hybridization
Gene Dosage
Telomere
Gene Deletion
Aneuploidy
Candida albicans
Pharmaceutical Preparations
Alleles

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Microbiology

Cite this

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.

In: Molecular Microbiology, Vol. 68, No. 3, 05.2008, p. 624-641.

Research output: Contribution to journalArticle

Selmecki, Anna ; Gerami-Nejad, Maryam ; Paulson, Carsten ; Forche, Anja ; Berman, Judith. / An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1. In: Molecular Microbiology. 2008 ; Vol. 68, No. 3. pp. 624-641.
@article{eea8b5bd560f40689f81135466380070,
title = "An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1",
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 (FluR). Comparative genome hybridization arrays revealed that the presence of two extra copies of Chr5L, on the isochromosome, conferred increased FluR and that partial truncation of Chr5L reduced FluR. 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 FluR 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.",
author = "Anna Selmecki and Maryam Gerami-Nejad and Carsten Paulson and Anja Forche and Judith Berman",
year = "2008",
month = "5",
doi = "10.1111/j.1365-2958.2008.06176.x",
language = "English",
volume = "68",
pages = "624--641",
journal = "Molecular Microbiology",
issn = "0950-382X",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1

AU - Selmecki, Anna

AU - Gerami-Nejad, Maryam

AU - Paulson, Carsten

AU - Forche, Anja

AU - Berman, Judith

PY - 2008/5

Y1 - 2008/5

N2 - 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 (FluR). Comparative genome hybridization arrays revealed that the presence of two extra copies of Chr5L, on the isochromosome, conferred increased FluR and that partial truncation of Chr5L reduced FluR. 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 FluR 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.

AB - 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 (FluR). Comparative genome hybridization arrays revealed that the presence of two extra copies of Chr5L, on the isochromosome, conferred increased FluR and that partial truncation of Chr5L reduced FluR. 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 FluR 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.

UR - http://www.scopus.com/inward/record.url?scp=41749113291&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41749113291&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2958.2008.06176.x

DO - 10.1111/j.1365-2958.2008.06176.x

M3 - Article

C2 - 18363649

AN - SCOPUS:41749113291

VL - 68

SP - 624

EP - 641

JO - Molecular Microbiology

JF - Molecular Microbiology

SN - 0950-382X

IS - 3

ER -