A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans

Détails

ID Serval
serval:BIB_D18DEFD4A327
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans
Périodique
Genetics
Auteur(s)
Coste  A., Turner  V., Ischer  F., Morschhauser  J., Forche  A., Selmecki  A., Berman  J., Bille  J., Sanglard  D.
ISSN
0016-6731 (Print)
Statut éditorial
Publié
Date de publication
04/2006
Volume
172
Numéro
4
Pages
2139-56
Notes
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't --- Old month value: Apr
Résumé
TAC1, a Candida albicans transcription factor situated near the mating-type locus on chromosome 5, is necessary for the upregulation of the ABC-transporter genes CDR1 and CDR2, which mediate azole resistance. We showed previously the existence of both wild-type and hyperactive TAC1 alleles. Wild-type alleles mediate upregulation of CDR1 and CDR2 upon exposure to inducers such as fluphenazine, while hyperactive alleles result in constitutive high expression of CDR1 and CDR2. Here we recovered TAC1 alleles from two pairs of matched azole-susceptible (DSY294; FH1: heterozygous at mating-type locus) and azole-resistant isolates (DSY296; FH3: homozygous at mating-type locus). Two different TAC1 wild-type alleles were recovered from DSY294 (TAC1-3 and TAC1-4) while a single hyperactive allele (TAC1-5) was isolated from DSY296. A single amino acid (aa) difference between TAC1-4 and TAC1-5 (Asn977 to Asp or N977D) was observed in a region corresponding to the predicted activation domain of Tac1p. Two TAC1 alleles were recovered from FH1 (TAC1-6 and TAC1-7) and a single hyperactive allele (TAC1-7) was recovered from FH3. The N977D change was seen in TAC1-7 in addition to several other aa differences. The importance of N977D in conferring hyperactivity to TAC1 was confirmed by site-directed mutagenesis. Both hyperactive alleles TAC1-5 and TAC1-7 were codominant with wild-type alleles and conferred hyperactive phenotypes only when homozygous. The mechanisms by which hyperactive alleles become homozygous was addressed by comparative genome hybridization and single nucleotide polymorphism arrays and indicated that loss of TAC1 heterozygosity can occur by recombination between portions of chromosome 5 or by chromosome 5 duplication.
Mots-clé
ATP-Binding Cassette Transporters/*genetics Alleles Antifungal Agents/*pharmacology Candida albicans/*genetics *Chromosomes, Fungal Drug Resistance, Microbial Fluphenazine/pharmacology Fungal Proteins/*genetics Heterozygote Homozygote *Loss of Heterozygosity Membrane Transport Proteins/*genetics Nucleic Acid Hybridization Polymorphism, Single Nucleotide Transcription Factors/chemistry/*genetics/physiology
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/01/2008 15:40
Dernière modification de la notice
20/08/2019 16:51
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