Aneuploidy and isochromosome formation in drug-resistant Candida albicans.
Resistance to the limited number of available antifungal drugs is a serious problem in the treatment of Candida albicans. We found that aneuploidy in general and a specific segmental aneuploidy, consisting of an isochromosome composed of the two left arms of chromosome 5, were associated with azole resistance. The isochromosome forms around a single centromere flanked by an inverted repeat and was found as an independent chromosome or fused at the telomere to a full-length homolog of chromosome 5. Increases and decreases in drug resistance were strongly associated with gain and loss of this isochromosome, which bears genes expressing the enzyme in the ergosterol pathway targeted by azole drugs, efflux pumps, and a transcription factor that positively regulates a subset of efflux pump genes.
Selmecki
Anna
A
Department of Genetics, Cell Biology, and Development, University of Minnesota, 6-160 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
Forche
Anja
A
Berman
Judith
J
D000782:Aneuploidy; D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development; D002503:Centromere / Q000648:ultrastructure; D015825:Chromosomes, Fungal; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000235:genetics*; D004875:Ergosterol / Q000096:biosynthesis; D015725:Fluconazole / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D018628:Gene Dosage; D020869:Gene Expression Profiling; D005800:Genes, Fungal; D018404:Isochromosomes; D007621:Karyotyping; D008969:Molecular Sequence Data; D012091:Repetitive Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014314:Trisomy
D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D014157:Transcription Factors; C465525:cytochrome P-450 CYP51, Candida albicans; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D004875:Ergosterol