Functional Characterization of DNA N-Glycosylase Ogg1 and Ntg1 in DNA Damage Stress of Cryptococcus neoformans

• Published in: The journal of microbiology 2023, 61(11), , pp.981-992
• Main Authors: Jung, Kwang-Woo, Kwon, Sunhak, Jung, Jong-Hyun, Lim, Sangyong, Bahn, Yong-Sun
• Format: Article
• Language: English
• Subjects: 8-Hydroxyguanine; Antifungal agents; Base excision repair; Biomedical and Life Sciences; Cryptococcus neoformans; Damage; Defects; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Drug resistance; Drugs; Fungal infections; Fungi; Fungicides; Gene deletion; Gene expression; Genes; Genomes; Genomics and Molecular Biology; Hog1 protein; Homologous recombination; Homology; Life Sciences; Microbial Genetics; Microbiology; Mutants; Mutation; Mutation rates; N-Glycosylase; Non-homologous end joining; Nucleotides; OGG1 protein; Oxidation; Oxidation resistance; Oxidative stress; Reactive oxygen species; Recombination; Thymine; Thymine glycol; 생물학
• ISSN: 1225-8873; 1976-3794
• DOI: 10.1007/s12275-023-00092-y

Reactive oxygen species induce DNA strand breaks and DNA oxidation. DNA oxidation leads to DNA mismatches, resulting in mutations in the genome if not properly repaired. Homologous recombination (HR) and non-homologous end-joining (NHEJ) are required for DNA strand breaks, whereas the base excision repair system mainly repairs oxidized DNAs, such as 8-oxoguanine and thymine glycol, by cleaving the glycosidic bond, inserting correct nucleotides, and sealing the gap. Our previous studies revealed that the Rad53-Bdr1 pathway mainly controls DNA strand breaks through the regulation of HR- and NHEJ-related genes. However, the functional roles of genes involved in the base excision repair system remain elusive in Cryptococcus neoformans . In the present study, we identified OGG1 and NTG1 genes in the base excision repair system of C. neoformans , which are involved in DNA oxidation repair. The expression of OGG1 was induced in a Hog1-dependent manner under oxidative stress. On the other hand, the expression of NTG1 was strongly induced by DNA damage stress in a Rad53-independent manner. We demonstrated that the deletion of NTG1 , but not OGG1 , resulted in elevated susceptibility to DNA damage agents and oxidative stress inducers. Notably, the ntg1 Δ mutant showed growth defects upon antifungal drug treatment. Although deletion of OGG1 or NTG1 did not increase mutation rates, the mutation profile of each ogg1 Δ and ntg1 Δ mutant was different from that of the wild-type strain. Taken together, we found that DNA N -glycosylase Ntg1 is required for oxidative DNA damage stress and antifungal drug resistance in C. neoformans .