DNA damage response of major fungal pathogen Candida glabrata offers clues to explain its genetic diversity

Abstract

How cells respond to DNA damage is key to maintaining genome integrity or facilitating genetic change. In fungi, DNA damage responses have been extensively characterized in the model budding yeast Saccharomyces cerevisiae, which is generally not pathogenic. However, it is not clear how closely these responses resemble those in fungal pathogens, in which genetic change plays an important role in the evolutionary arms race between pathogen and host and the evolution of antifungal drug resistance. A close relative of S. cerevisiae, Candida glabrata, is an opportunistic pathogen that displays high variability in chromosome structure among clinical isolates and rapidly evolves antifungal drug resistance. The mechanisms facilitating such genomic flexibility and evolvability in this organism are unknown. Recently we characterized the DNA damage response of C. glabrata and identified several features that distinguish it from the well characterized DNA damage response of S. cerevisiae. First, we discovered that, in contrast to the established paradigm, C. glabrata effector kinase Rad53 is not hyperphosphorylated upon DNA damage. We also uncovered evidence of an attenuated DNA damage checkpoint response, wherein in the presence of DNA damage C. glabrata cells did not accumulate in S-phase and proceeded with cell division, leading to aberrant mitoses and cell death. Finally, we identified evidence of transcriptional rewiring of the DNA damage response of C. glabrata relative to S. cerevisiae, including an upregulation of genes involved in mating and meiosis-processes that have not been reported in C. glabrata. Together, these results open new possibilities and raise tantalizing questions of how this major fungal pathogen facilitates genetic change.

Keywords: Candida glabrata; DNA damage checkpoint; DNA damage response; Genome stability; HO endonuclease; Mating; Meiosis; Rad53.

Figure 1.. DNA damage-induced transcriptional changes of C. glabrata orthologs of genes involved in sexual reproduction.

The color scheme represents transcript abundance log2 ratios (MMS/no MMS). The RNAseq data are available at the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE155701) and have been previously described (Shor, et al. 2020). The heatmaps were generated using the R studio gplots package.

Figure 2.. Schematic representation of the differences between the responses to DNA damage () in C. glabrata and S. cerevisiae.