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

Kundan Kumar1,2, Romila Moirangthem1, Rupinder Kaur1

  • 1Laboratory of Fungal Pathogenesis, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.

Plos Genetics
|March 6, 2020
PubMed

Insights

Candida glabrata uses DNA repair mechanisms to survive oxidative stress. Researchers found that controlling histone H4 levels is crucial for homologous recombination (HR) pathway activation and methyl methanesulfonate (MMS) resistance in this fungal pathogen.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Genetics

Background:

  • Candida glabrata is a significant nosocomial fungal pathogen responsible for bloodstream infections.
  • Its virulence is linked to macrophage replication and oxidative stress survival.
  • The role of DNA repair in C. glabrata's pathogenicity is under investigation.

Purpose of the Study:

  • To characterize the DNA damage response of C. glabrata to methyl methanesulfonate (MMS).
  • To elucidate the involvement of histone H4 and homologous recombination (HR) in MMS resistance.
  • To identify key proteins regulating these pathways.

Main Methods:

  • Exposure of C. glabrata to MMS to induce DNA damage.
  • Analysis of histone H4 transcript and protein levels.
  • Assessment of homologous recombination (HR) frequency and MMS resistance.
  • Genetic analysis involving CgRad52.
  • Tandem-affinity purification and mass spectrometry to identify H4 interactors.
  • Genetic and physical interaction studies with CgCmr1.

Main Results:

  • MMS exposure downregulated histone H4 levels.
  • DNA damage was repaired via the homologous recombination (HR) pathway.
  • Reduced H4 gene dosage correlated with increased HR frequency and MMS resistance.
  • CgRad52 is essential for MMS resistance.
  • CgCmr1 interacts with H4, regulating H4 levels, HR, and MMS survival.

Conclusions:

  • Histone H4 levels are tightly regulated in C. glabrata as a mechanism for surviving MMS-induced DNA damage.
  • The HR pathway, involving CgRad52 and CgCmr1, plays a critical role in this stress response.
  • Understanding these mechanisms can inform strategies against C. glabrata infections.

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