Histone H4 dosage modulates DNA damage response in the pathogenic yeast Candida glabrata via homologous recombination pathway

English version

Autoři: Kundan Kumar ^aff001; Romila Moirangthem ^aff001; Rupinder Kaur ^aff001
Působiště autorů: Laboratory of Fungal Pathogenesis, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India ^aff001; Graduate studies, Manipal Academy of Higher Education, Manipal, Karnataka, India ^aff002
Vyšlo v časopise: Histone H4 dosage modulates DNA damage response in the pathogenic yeast Candida glabrata via homologous recombination pathway. PLoS Genet 16(3): e32767. doi:10.1371/journal.pgen.1008620
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008620

Souhrn

Candida glabrata, a nosocomial fungal bloodstream pathogen, causes significant morbidity and mortality in hospitals worldwide. The ability to replicate in macrophages and survive a high level of oxidative stress contributes to its virulence in the mammalian host. However, the role of DNA repair and recombination mechanisms in its pathobiology is still being discovered. Here, we have characterized the response of C. glabrata to the methyl methanesulfonate (MMS)-induced DNA damage. We found that the MMS exposure triggered a significant downregulation of histone H4 transcript and protein levels, and that, the damaged DNA was repaired by the homologous recombination (HR) pathway. Consistently, the reduced H4 gene dosage was associated with increased HR frequency and elevated resistance to MMS. The genetic analysis found CgRad52, a DNA strand exchange-promoter protein of the HR system, to be essential for this MMS resistance. Further, the tandem-affinity purification and mass spectrometry analysis revealed a substantially smaller interactome of H4 in MMS-treated cells. Among 23 identified proteins, we found the WD40-repeat protein CgCmr1 to interact genetically and physically with H4, and regulate H4 levels, HR pathway and MMS stress survival. Controlling H4 levels tightly is therefore a regulatory mechanism to survive MMS stress in C. glabrata.

Klíčová slova:

DNA damage – DNA repair – DNA-binding proteins – Gene expression – Histones – Homologous recombination – Chromatin – Saccharomyces cerevisiae

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