The histone acetyltransferase Hat1 facilitates DNA damage repair and morphogenesis in Candida albicans.
Chromatin assembly and remodelling is an important process during the repair of DNA damage in eukaryotic cells. Although newly synthesized histone H4 is acetylated prior to nuclear import and incorporation into chromatin during DNA damage repair, the precise role of acetylation in this process is poorly understood. Here, we identify the histone acetyltransferase 1 (Hat1) catalysing the conserved acetylation pattern of histone H4 preceding its chromatin deposition in the fungal pathogen Candida albicans. Surprisingly, Hat1 is required for efficient repair of not just exogenous but also endogenous DNA damage. Cells lacking Hat1 rapidly accumulate DNA damages and switch from yeast-like to pseudohyphal growth. In addition, reduction of histone H4 mimics lack of Hat1, suggesting that inefficient H4 supply for deposition into chromatin is the key functional consequence of Hat1 deficiency. Thus, remarkably, we demonstrate that C. albicans is the first organism known to require histone H4 processing for endogenous DNA damage repair and morphogenesis. Strikingly, we also discover that hat1Δ/Δ cells are hypersusceptible to caspofungin due to intracellular reactive oxygen species induced by this drug. Hence, we propose that targeting this class of histone acetyltransferases in fungal pathogens may have potential in antifungal therapy.
Medical University of Vienna, Christian Doppler Laboratory for Infection Biology, Max F. Perutz Laboratories, Campus Vienna Biocenter, A-1030 Vienna, Austria.
Michael
M
Tscherner
Eva
E
Stappler
Denes
D
Hnisz
Karl
K
Kuchler
D000935:Antifungal Agents / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D000077336:Caspofungin; D042002:Chromatin Assembly and Disassembly; D004249:DNA Damage; D004260:DNA Repair; D054714:Echinocandins / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D055666:Lipopeptides; D008826:Microbial Sensitivity Tests; D009024:Morphogenesis
D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D006657:Histones; D055666:Lipopeptides; D051548:Histone Acetyltransferases; C110880:histone acetyltransferase type B complex; D000077336:Caspofungin