Abstract
Fungal infections have far-reaching implications that range from severe human disease to a panoply of disruptive agricultural and ecological effects, making it imperative to identify and understand the molecular pathways governing the response to antifungal compounds. In this context, CZT-1 (cell death-activated zinc cluster transcription factor) functions as a master regulator of cell death and drug susceptibility in Neurospora crassa. Here we provide evidence indicating that czt-1 is allelic to acr-3, a previously described locus that we now found to harbor a point mutation in its coding sequence. This nonsynonymous amino acid substitution in a low complexity region of CZT-1/ACR-3 caused a robust gain-of-function that led to reduced sensitivity to acriflavine and staurosporine, and increased expression of the drug efflux pump abc-3. Thus, accumulating evidence shows that CZT-1 is an important broad regulator of the cellular response to various antifungal compounds that appear to share common molecular targets.
Highlights
Human fungal infections have been, until recently, a largely underestimated public health problem with dramatic worldwide ramifications
We show that a single amino acid change in czt-1 results in gain-of-function and is the likely cause for the enhanced tolerance to acriflavine of the acr-3 strain
The application of classical forward genetics methodologies in N. crassa has resulted in a collection of strains displaying morphological and developmental phenotypes that has been complemented with a genetic map of more than 1000 phenotypic markers and hundreds of other features like telomeres, centromeres, nucleolus organizer region, translocations, inversions and duplications [14]
Summary
Human fungal infections have been, until recently, a largely underestimated public health problem with dramatic worldwide ramifications. We report that czt-1 is allelic to acr-3, a locus that had been described in a mutant N. crassa strain obtained decades ago by random mutagenesis and that exhibits increased resistance to the fungal growth inhibitors acriflavine and malachite green [11].
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