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Reference: Legrand M, et al. (2007) Role of DNA Mismatch Repair and Double-Strand Break Repair in Genome Stability and Antifungal Drug Resistance in Candida albicans. Eukaryot Cell 6(12):2194-205

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Abstract


Drug resistance has become a major problem in the treatment of Candida albicans infections. Genome changes, such as aneuploidy, translocations, loss of heterozygosity, or point mutations, are often observed in clinical isolates that have become resistant to antifungal drugs. To determine whether these types of alterations result when DNA repair pathways are eliminated, we constructed yeast strains bearing deletions in six genes involved in Mismatch Repair (MSH2 and PMS1) or Double-Strand Break Repair (MRE11, RAD50, RAD52 and YKU80). We show that the mre11Delta/Delta, rad50Delta/Delta and rad52Delta/Delta mutants are slow-growing, exhibit a wrinkly colony phenotype, and cultures of these mutants contain abundant elongated pseudohyphal-like cells. These same mutants are susceptible to hydrogen peroxide, tetrabutyl hydrogen peroxide (TBHP), ultraviolet radiation (UV), camptothecin, ethylmethane sulfonate (EMS), and methylmethane sulfonate (MMS). The msh2Delta/Delta, pms1Delta/Delta and yku80Delta/Delta mutants exhibit none of these phenotypes. We observed an increase in genome instability in mre11Delta/Delta and rad50Delta/Delta mutants, using a GAL1/URA3 marker system to monitor the integrity of chromosome 1. We investigated the acquisition of drug resistance in the DNA repair mutants and found that deletion of mre11Delta/Delta, rad50Delta/Delta and rad52Delta/Delta leads to an increased susceptibility to fluconazole. Interestingly, we also observed an elevated frequency of appearance of drug resistant colonies for both msh2Delta/Delta and pms1Delta/Delta (MMR mutants) and rad50Delta/Delta (DSBR mutant). Our data demonstrate that defects in double-strand break repair lead to an increase in genome instability, while drug-resistant Candida albicans arise more rapidly in strains lacking mismatch repair proteins or proteins central to double-strand break repair.

Reference Type
Journal Article
Authors
Legrand M, Chan CL, Jauert PA, Kirkpatrick DT
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