Abstract
ABSTRACTThe basidiomycetous fungus Cryptococcus neoformans has been known to be highly radiation resistant and has been found in fatal radioactive environments such as the damaged nuclear reactor at Chernobyl. To elucidate the mechanisms underlying the radiation resistance phenotype of C. neoformans, we identified genes affected by gamma radiation through genome-wide transcriptome analysis and characterized their functions. We found that genes involved in DNA damage repair systems were upregulated in response to gamma radiation. Particularly, deletion of recombinase RAD51 and two DNA-dependent ATPase genes, RAD54 and RDH54, increased cellular susceptibility to both gamma radiation and DNA-damaging agents. A variety of oxidative stress response genes were also upregulated. Among them, sulfiredoxin contributed to gamma radiation resistance in a peroxiredoxin/thioredoxin-independent manner. Furthermore, we found that genes involved in molecular chaperone expression, ubiquitination systems, and autophagy were induced, whereas genes involved in the biosynthesis of proteins and fatty acids/sterols were downregulated. Most importantly, we discovered a number of novel C. neoformans genes, the expression of which was modulated by gamma radiation exposure, and their deletion rendered cells susceptible to gamma radiation exposure, as well as DNA damage insults. Among these genes, we found that a unique transcription factor containing the basic leucine zipper domain, named Bdr1, served as a regulator of the gamma radiation resistance of C. neoformans by controlling expression of DNA repair genes, and its expression was regulated by the evolutionarily conserved DNA damage response protein kinase Rad53. Taken together, the current transcriptome and functional analyses contribute to the understanding of the unique molecular mechanism of the radiation-resistant fungus C. neoformans.
Highlights
The basidiomycetous fungus Cryptococcus neoformans has been known to be highly radiation resistant and has been found in fatal radioactive environments such as the damaged nuclear reactor at Chernobyl
We demonstrated that the expression levels of RAD51, RAD54, RDH54, and PSO2 genes were significantly increased during gamma radiation (Fig. 2A)
Our transcriptome analysis revealed that the expression levels of genes involved in DNA repair systems, molecular chaperones, and proteasomes were induced, while those involved in protein translation, metabolic process, and ergosterol synthesis were reduced in response to gamma radiation
Summary
We found that genes involved in DNA damage repair systems were upregulated in response to gamma radiation. Various types of DNA lesions, including base modification, abasic sites, and strand breaks, are caused by the interaction of OH· with DNA and direct ionization of the DNA molecules, normally resulting in detrimental effects on cell survival [1] To counteract these fatal effects, cells activate arrays of DNA repair machineries and antioxidative defense systems, and if the IR-induced damage exceeds the capacity of cells to repair it, the cells die. D. radiodurans has various DNA repair systems, including extended synthesis-dependent strand annealing and the RecF pathway of homologous recombination (HR), which can efficiently repair DNA double-strand breaks (DSBs), considered to be the most lethal form of damage This organism removes ROS through enzymatic systems, such as superoxide dismutase, catalase, and peroxidase, and nonenzymatic systems, such as pyrroloquinoline-quinone, deinoxanthin, and bacillithiol [5, 6]. There has been no systematic and comprehensive approach to elucidating the radiation resistance mechanism of C. neoformans
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