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.
Candida albicans is the most prevalent fungal pathogen causing disease in humans;systemic infections have a mortality rate in the USA of up to fifty percent, despite the use of currently available antifungal drugs. This proposal will study basic mechanisms of genome instability, a feature of antifungal drug resistance in C. albicans as well as a hallmark of mammalian cancers. The research proposed here will explore the use of anti-cancer drugs as potential companion drugs, with the goal of extending the usefulness of existing antifungal therapies.
|Hickman, Meleah A; Paulson, Carsten; Dudley, Aimee et al. (2015) Parasexual Ploidy Reduction Drives Population Heterogeneity Through Random and Transient Aneuploidy in Candida albicans. Genetics 200:781-94|
|Tsai, Hung-Ji; Baller, Joshua A; Liachko, Ivan et al. (2014) Origin replication complex binding, nucleosome depletion patterns, and a primary sequence motif can predict origins of replication in a genome with epigenetic centromeres. MBio 5:e01703-14|
|Hickman, Meleah A; Zeng, Guisheng; Forche, Anja et al. (2013) The 'obligate diploid' Candida albicans forms mating-competent haploids. Nature 494:55-9|