Genomic hypermutability in Candida albicans

University Of Minnesota, Minneapolis MN

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Abstract

DESCRIPTION (provided by applicant): Genome instability is a fundamental process that underpins tumor progression, evasion of host defenses by pathogens and resistance to drugs ranging from antibiotics to antifungals and chemotherapeutic agents. Moreover, exposure to stress often increases genome instability in a process known as stress-induced mutagenesis, and switches a subpopulation of cells to a hyper-mutagenic state, which has been characterized primarily in bacteria. Here, I will study stress-induced mutagenesis in a eukaryotic pathogen, Candida albicans. C. albicans is a common component of the gut microflora that is also the most prevalent fungal pathogen of humans. Important for this work, it is extremely susceptible to, and tolerant of, genomic perturbations and is amenable to study at the genetic, molecular, population and genomic levels. Moreover, there is a limited arsenal of anti-fungal drugs available; in patients that receive long-term antifungal drug treatment, C. albicans can rapidly acquire drug resistance. This resistance frequently arises by major genome changes (e.g. loss of heterozygosity or aneuploidy, an imbalance in the number of chromosomes). In this proposal, I will 1) determine if antifungal drugs and other stresses increase the frequency with which cells are hyper-mutagenic and acquire multiple mutations; 2) determine if specific types of mutations are more common in hyper-mutagenic cells; and 3) determine whether genetic pathways that contribute to genome stability in cancer cells also affect stress-induced mutagenesis in C. albicans. In addition I will identify drug candidates that alter rates of stress-induced mutagenesis in C. albicans cells with the goal of identifying candidate compounds that reduce the frequency with which antifungal resistance is acquired. This study will provide mechanistic information on how mutations arise in the presence of stress and also will identify candidate companion drugs that could be administered together with existing antifungals to extend their useful lifespan.