A non-canonical DNA damage checkpoint response in a major fungal pathogen

To protect genome integrity, eukaryotic cells respond to DNA damage by triggering highly conserved checkpoint mechanisms involving the phosphorylation of Rad53/CHK2 kinase. Budding yeast Candida glabrata, closely related to model eukaryote Saccharomyces cerevisiae, is an opportunistic pathogen characterized by high genetic diversity and rapid emergence of drug resistant mutants. However, the mechanisms enabling this genetic variability are unclear. Here we show that C. glabrata cells exposed to DNA damage neither induce CgRad53 phosphorylation nor accumulate in S phase, and exhibit higher lethality than S. cerevisiae. Furthermore, time-lapse microscopy showed C. glabrata cells continuing to divide in the presence of DNA damage, resulting in mitotic errors and cell death. Finally, RNAseq analysis revealed transcriptional rewiring of the DNA damage response in C. glabrata and identified several key protectors of genome stability upregulated by DNA damage in S. cerevisiae but downregulated in C. glabrata, including PCNA. Together, our results reveal a non-canonical fungal DNA damage response, which may contribute to rapidly generating genetic change and drug resistance.