DNA damage repair factor Rad18 controls virulence partially via transcriptional suppression of genes <i>HWP1</i> and <i>ECE1</i> in <i>Candida albicans</i>

DNA damage repair is a crucial cellular mechanism for rectifying DNA lesions arising during growth and development, making it essential for pathogens to combat the reactive oxygen species (ROS) stress generated by host cells. Among the various repair pathways, postreplication repair (PRR) plays a pivotal role in resolving single-stranded gaps induced by DNA damage. However, the contribution of PRR to virulence remain elusive in the fungal pathogen <i>Candida albicans</i><i> </i><i>(C. albicans)</i>. In this study, we investigated the role of Rad18, a critical component of PRR, in DNA damage response and virulence in <i>C. albicans</i>. We observed that deletion of <i>RAD18</i> in <i>C. albicans</i> resulted in heightened sensitivity to DNA damage stress. Through deletion of specific internal domains coupled with spot assay analysis, our findings revealed that the internal RING and SAP domains played essential roles in DNA damage response, whereas the ZNF domain exhibited relatively less importance. Using the <i>Galleria mellonella</i> model, loss of Rad18 led to increased virulence. RNA-seq analysis revealed that loss of Rad18 upregulated the transcription of genes encoding transporters and oxidoreductases, as well as virulence genes, including <i>HWP1</i> and <i>ECE1</i>. Suppression of the transcription of these virulence genes in the <i>RAD18</i>-deletion strain by a dCas9-mediated CRISPRi system reversed its increased virulence. Taken together, these data demonstrate that Rad18 plays a significant role in virulence partially through transcriptional suppression of virulence genes <i>HWP1</i> and <i>ECE1</i> in <i>C. albicans</i>. Our findings provide valuable insights into the intricate relationship between DNA damage response and virulence in <i>C. albicans</i>.