25 June 2012 00:00 hrs.
Control of histone acetylation as a novel anti-fungal therapeutic strategy

Dr. Alain Verreault, Institute for Research in Immunology and Cancer Institute, Montreal, Canada


Dr. Colin Logie, Department of Molecular Biology, NCMLS, Nijmegen

25-06-2012 00:00:00Europe/AmsterdamControl of histone acetylation as a novel anti-fungal therapeutic strategy

Remarks / more information:

Verreault, AlainCandida albicansis a commensal yeast that colonises the gastro-intestinal tract but is harmless to healthy individuals. This is due to constant immunosurveillance that prevents systemic dissemination and invasion of vital organs. However, immunocompromised individuals, such as those undergoing organ transplantation or cancer chemotherapy, often suffer from life-threatening infections. Although some pharmacological agents are available to treatC. albicansinfections, the emergence of drug-resistant strains and hospital-acquired infections by healthy individuals is a growing concern for health care organisations.

Histone H3 lysine acetylation (H3K56ac) is a genome-wide feature of yeast chromosomes. H3K56ac is regulated by fungal-specific enzymes, thus making these enzymes appealing targets for antifungal therapy. Interestingly, yeast cells lacking H3K56ac and, to an even greater extent, cells with genome-wide H3K56ac, exhibit a high incidence of spontaneous DNA damage. H3K56ac is acetylated by Rtt109 and deacetylated by Hst3. In C. albicans, inhibition of Hst3 results in a dramatic loss of cell viability associated with anomalous histone degradation and aberrant DNA staining that likely reflects catastrophic DNA damage. Using genetic and pharmacological approaches, we demonstrate that inhibition of H3K56 deacetylation reduces virulence in a mouse model of C. albicans infection. Our results suggest that modulation of H3K56ac may prove valuable to treat C.albicans, and possibly other fungal infections.

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