Variation and conformity in the iron limitation response among Candida albicans strains

In human fungal pathogen Candida albicans, three transcription factors Sef1, Hap43, and Sfu1 work in concert to control iron acquisition and utilization genes. We hypothesized that iron regulatory networks may be subject to within-species rewiring or rebalancing. We constructed sef1dd, hap43dd and sfu1dd mutants in five C. albicans clinical isolates with distinct lineages and assayed their growth and gene expression phenotypes. Our findings indicate that Sef1 is required in all five strains for growth under iron limitation, and that it is required for induction of iron acquisition genes. However, the severity of mutant phenotypes varies with strain background. The global transcriptional response to low iron in two strains examined suggested that iron limitation may induce DNA damage, particularly in sef1dd strains. DNA damage might result from defective activities of iron-dependent DNA replication and repair proteins, including DNA polymerases, DNA helicases, and ribonucleotide reductase. We tested this hypothesis with assays for loss of heterozygosity (LOH) of mutations in ADE2 and URA3. Results of LOH assays support our hypothesis. All in all, our work demonstrates that iron regulator Sef1 plays a critical role in genome integrity during iron limitation, likely a result of its role in iron acquisition.