Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy
| Autor: | Martine Raymond, Paul Drogaris, Alaka Mullick, Guylaine Lépine, Eun Hye Lee, Alain Verreault, Hugo Wurtele, Pierre Thibault, Sarah Tsao, Jessy Tremblay |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
yeast
Histones immunology Drug Delivery Systems inhibitors saccharomyces cerevisiae Candida albicans Histone Acetyltransferases Fungal protein biology diffusion Acetylation in vitro General Medicine vitro Corpus albicans nucleic acids Histone Acetyltransferase candida acid antifungal agents cell cycle epidemiology biotechnology Niacinamide skin mice Cell Survival mouse model enzymes DNA replication chemistry Histone Deacetylases General Biochemistry Genetics and Molecular Biology Article Microbiology Fungal Proteins Histone H3 sirtuins Animals mammals gene genome therapy activity flow cytometry aging DNA cell biology.organism_classification candidiasis Molecular biology virulence gene expression biology.protein RNA candida albicans protein |
| Popis: | Candida albicans is a major fungal pathogen that causes serious systemic and mucosal infections in immunocompromised individuals. In yeast, histone H3 Lys56 acetylation (H3K56ac) is an abundant modification regulated by enzymes that have fungal-specific properties, making them appealing targets for antifungal therapy. Here we demonstrate that H3K56ac in C. albicans is regulated by the RTT109 and HST3 genes, which respectively encode the H3K56 acetyltransferase (Rtt109p) and deacetylase (Hst3p). We show that reduced levels of H3K56ac sensitize C. albicans to genotoxic and antifungal agents. Inhibition of Hst3p activity by conditional gene repression or nicotinamide treatment results in a loss of cell viability associated with abnormal filamentous growth, histone degradation and gross aberrations in DNA staining. We show that genetic or pharmacological alterations in H3K56ac levels reduce virulence in a mouse model of C. albicans infection. Our results demonstrate that modulation of H3K56ac is a unique strategy for treatment of C. albicans and, possibly, other fungal infections. -¬ 2010 Nature America, Inc. All rights reserved |
| Databáze: | OpenAIRE |
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