An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1.
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.
Selmecki
Anna
A
Department of Genetics, Cell and Development, University of Minnesota, Minneapolis, MN 55305, USA.
Gerami-Nejad
Maryam
M
Paulson
Carsten
C
Forche
Anja
A
Berman
Judith
J
D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics*; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology*; D015825:Chromosomes, Fungal / Q000235:genetics; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000494:pharmacology* / Q000627:therapeutic use; D005656:Fungal Proteins / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D005784:Gene Amplification; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D018404:Isochromosomes; D008826:Microbial Sensitivity Tests; D016366:Open Reading Frames; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide
D000935:Antifungal Agents; D005656:Fungal Proteins; D015725:Fluconazole