Disconnecting a Role for DNA Repair in the Pathogenicity of the Human pathogen Cryptococcus neoformans

Abstract

C. neoformans is an opportunistic fungal pathogen causing fatal meningitis and lung infections. Worldwide every year around 625,000 deaths occur due to Cryptococcosis. A basic understanding of Cryptococcus virulence mechanisms and survival strategies is required to combat the infections and develop therapies through translational research. Considering the evidence of a role of DNA repair in pathogenesis, I investigated DNA repair strategies adopted by Cryptococcus to survive in the environment and to cause successful infection. The repair of UV induced DNA damage was studied for two genes: UVE1 and RAD23, parts of base excision repair and nucleotide excision repair pathways, respectively. My findings suggest that UVE1 is required to combat UV induced stress. Uve1 is a mitochondrially-localized enzyme that functions to protect the mitochondrial genome from the deleterious effects of UV-induced DNA damage. Another aspect explored was the regulation of UVE1 by the Bwc1-Bwc2 photoreceptor complex. UVE1 is a direct downstream target of Bwc1-Bwc2 and is responsible for the UV sensitivity phenotype governed by this complex, without affecting mating or virulence. The regulation of UVE1 iv through the Bwc1-Bwc2 photoreceptor was also extended to two other fungal lineages, ascomycetes and zygomycetes. The second DNA repair gene, RAD23, codes for a dual function protein acting in nucleotide excision repair and as an ubiquitin receptor. Those two functions were uncoupled by creating mutant alleles and testing the strains carrying them for their virulence. The DNA repair function of the Rad23 is dispensable for virulence. Hence, specific DNA repair pathways do not necessarily have a major role in the virulence of Cryptococcus. However, ancillary functions of a DNA repair protein can contribute to virulence.