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Eukaryotic Cell, December 2007, p. 2194-2205, Vol. 6, No. 12
1535-9778/07/$08.00+0     doi:10.1128/EC.00299-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Role of DNA Mismatch Repair and Double-Strand Break Repair in Genome Stability and Antifungal Drug Resistance in Candida albicans

Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455

Received 14 August 2007/ Accepted 11 October 2007

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 mre11/mre11, rad50/rad50, and rad52/rad52 mutants are slow growing and exhibit a wrinkly colony phenotype and that cultures of these mutants contain abundant elongated pseudohypha-like cells. These same mutants are susceptible to hydrogen peroxide, tetrabutyl hydrogen peroxide, UV radiation, camptothecin, ethylmethane sulfonate, and methylmethane sulfonate. The msh2/msh2, pms1/pms1, and yku80/yku80 mutants exhibit none of these phenotypes. We observed an increase in genome instability in mre11/mre11 and rad50/rad50 mutants by 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 mre11/mre11, rad50/rad50, or rad52/rad52 leads to an increased susceptibility to fluconazole. Interestingly, we also observed an elevated frequency of appearance of drug-resistant colonies for both msh2/msh2 and pms1/pms1 (MMR mutants) and rad50/rad50 (DSBR mutant). Our data demonstrate that defects in double-strand break repair lead to an increase in genome instability, while drug resistance arises more rapidly in C. albicans strains lacking mismatch repair proteins or proteins central to double-strand break repair.

Published ahead of print on 26 October 2007.

This article has been cited by other articles:

• Legrand, M., Chan, C. L., Jauert, P. A., Kirkpatrick, D. T. (2008). Analysis of base excision and nucleotide excision repair in Candida albicans. Microbiology 154: 2446-2456 [Abstract] [Full Text]