Critical roles of Dpb3-Dpb4 sub-complex of DNA polymerase epsilon in DNA replication, genome stability, and pathogenesis of Candida albicans

DNA polymerase ε (Polε) is an essential replicative polymerase consisting of Pol2, Dpb2, Dpb3, and Dpb4 subunits and has not been explored in the pathogenic yeast is accountable for >40% of deaths due to systemic candidiasis per year worldwide. Genome plasticity is one of the adaptive mechanisms associated with virulence, and as it is associated with DNA polymerase function, this study explored the role of Polε in genome stability and pathogenesis of and are haploinsufficient, but and are dispensable for cell survival in diploid . However, unlike in , loss of any or both of the nonessential subunits or defective interaction between the two resulted in slow growth and temperature-sensitive phenotypes. Knockout strains of ΔΔ and ΔΔ and ΔΔ ΔΔ) also exhibited sensitivity to genotoxic agents and delayed cell cycle progression. Reduced processive DNA synthesis and increased rate of mutagenesis were observed in and null strains. Whole-genome sequencing further confirmed the accumulation of indels and SNPs majorly in the intergenic repeat regions of the chromosomes of ΔΔ ΔΔ. Polε-defective strains were constitutively filamentous and non-pathogenic in mice models of systemic candidiasis. Altogether, this study showed that the function of the Dpb3-Dpb4 subcomplex is critical for fungal morphogenesis and virulence besides its role as a structural component of Polε in DNA replication and genome stability; thus, their interacting interface may be targeted to develop antifungal drugs. This study explored the role of DNA polymerase epsilon, especially its non-essential structural subunits in biology. Apart from their role in DNA replication and genome stability, the Dpb3-Dpb4 subcomplex regulates morphological switching and virulence. Since the defective strain is locked in filamentous form and is avirulent, the complex may be targeted for anti-fungal drug development.