The genotoxic stress-inducible gene GEI1(Orf19.3109) is a repressor of virulence in Candida albicans

Transcriptional reprogramming under genotoxic stress is essential for the survival and pathogenesis of Candida albicans. While many DNA damage response (DDR) genes are well-characterized, the functions of pathogen-specific, stress-inducible genes remain enigmatic. Here, we characterized GEI1 (Orf19.3109), a gene robustly induced by genotoxic agents and oxidative stress, which lacks a discernible ortholog in Saccharomyces cerevisiae. Unexpectedly, although GEI1 expression is triggered by DNA damage, its deletion does not impair genotoxin tolerance. Instead, the gei1Δ/Δ mutant exhibits a striking increase in resistance to oxidative stress, characterized by reduced intracellular reactive oxygen species (ROS) accumulation and attenuated apoptosis. Furthermore, loss of GEI1 leads to massive hyper-secretion of extracellular aspartyl proteases (Saps) and displays an extreme hypervirulence phenotype in the Galleria mellonella infection model. Integrated transcriptomic profiling and CRISPR-interference (CRISPRi) assays revealed that GEI1 functions as a negative regulator of the antioxidant-defense axis and proteolytic enzyme secretion. We demonstrate that the hypervirulence of the gei1Δ/Δ strain is primarily driven by the transcriptional de-repressions of SAP1, SAP3 and SAP5 and the putative alcohol dehydrogenase ADH4. Repression of these downstream effectors in the gei1Δ/Δ background successfully restricted protease hyper-secretion and restored fungal virulence to wild-type levels. Our findings uncouple transcriptional induction from conventional DNA repair functions and reveal a novel regulatory checkpoint where GEI1 links genotoxic stress signaling to the suppression of key pathogenic traits in C. albicans.