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The role of Dnj4 in the transcriptional response to hydroxyurea induced DNA damage in Cryptococcus neoformans

ABSTRACT: We characterized the impact of the J domain co-chaperone, Dnj4, on the transcriptional response to DNA damage induced by hydroxyurea (an inhibitor of ribonucleotide reductase) in Cryptococcus neoformans. We treated wild type (WT) and mutant dnj4∆ log phase cells with hydroxyurea for one hour and found that the loss of DNJ4 impaired the transcriptional response to HU. In particular, the up-regulation of DNA damage and repair genes as well as iron uptake genes was impaired in these mutants. This study provides the first dataset on the transcriptional response to hydroxyurea in C. neoformans as a resource to the fungal pathogen community.

ORGANISM(S): Cryptococcus neoformans var. grubii H99

PROVIDER: GSE182879 | GEO | 2021/12/09

REPOSITORIES: GEO

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Project description:The target of rapamycin (TOR) pathway is an evolutionarily conserved signal transduction system that is activated by varying nutrient and environmental signals and governs a plethora of eukaryotic biological processes. Nevertheless, its role in the human fungal pathogen Cryptococcus neoformans remains elusive. In this study, we investigated the TOR pathway by functionally characterizing two Tor-like kinases, Tor1 and Tlk1, in C. neoformans. We successfully deleted TLK1, but not TOR1. TLK1 deletion did not result in any evident in vitro phenotypes, except for a minor role in diamide and polyene resistance, suggesting that Tlk1 is mainly dispensable for the growth of C. neoformans. We further demonstrated that Tor1, but not Tlk1, is essential and the target of rapamycin by constructing and analyzing conditionally regulated strains and sporulation analysis of heterozygous mutants in the diploid strain background. To analyze the functions of Tor1 in more detail, we constructed constitutive TOR1 overexpression strains. Tor1 negatively regulated thermotolerance and the DNA damage response, which are two important virulence factors of C. neoformans. We also found that TOR1 overexpression reduced Mpk1 phosphorylation, which is required for cell wall integrity and thermoresistance, and Rad53 phosphorylation, which governs the DNA damage response pathway. Tor1 is localized to the cytoplasm but enriched in the vacuole membrane. Phosphoproteomics and transcriptomics revealed that Tor1 regulates a variety of biological processes, including metabolic processes, cytoskeleton organization, ribosome biogenesis, autophagy, and stress response. Finally, screening rapamycin-sensitive and -resistant kinase and transcription factor mutants revealed that the TOR pathway may crosstalk with a number of signaling pathways, including the Hog1 pathway. In conclusion, our study demonstrates that a single Tor1 kinase plays a variety of roles in the fungal meningitis pathogen C. neoformans.

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The role of Dnj4 in the transcriptional response to hydroxyurea induced DNA damage in Cryptococcus neoformans

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