Functional Roles of Dnl4, DNA Ligase IV, in DNA Damage Stress in a Radiation-resistant Fungus, Cryptococcus neoformans
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One of the significant biological effects of radiation is the genetic damage caused by DNA double strandbreaks (DSBs), which can lead to mutations or cell death. To repair DNA damage, living things contain diverse andelaborate DNA repair systems, including homologous recombination (HR) and non-homologous end joining (NHEJ)that have been extensively studied across species, from yeast to humans. Cryptococcus has been utilized as a modelorganism in the studies of radiation response and DNA damage repair due to its radiation-resistance. This studyfocuses on the identification and characterization of the DNL4 gene, encoding DNA ligase IV in the NHEJ pathway,in C. neoformans. We found that expression level of DNL4 was induced in response to DNA damage stress and wasdependent on the Rad53-Bdr1 pathway. Both deletions of DNL4 and RAD51 rendered strains more susceptible toradiation than each mutant, indicating that HR and NHEJ play redundant roles in DNA damage response. In addition,DNL4 was also increased under H2O2or tBOOH treatment although its deletion did not affect resistance to them. Perturbation of DNL4 increased microevolution, suggesting its potential role in genetic stability. However, dnl4∆mutant exhibited WT-levels of hyphal growth production. Taken together, C. neoformans Dnl4 plays roles in DNAdamage response and microevolution.
Abstract
One of the significant biological effects of radiation is the genetic damage caused by DNA double strandbreaks (DSBs), which can lead to mutations or cell death. To repair DNA damage, living things contain diverse andelaborate DNA repair systems, including homologous recombination (HR) and non-homologous end joining (NHEJ)that have been extensively studied across species, from yeast to humans. Cryptococcus has been utilized as a modelorganism in the studies of radiation response and DNA damage repair due to its radiation-resistance. This studyfocuses on the identification and characterization of the DNL4 gene, encoding DNA ligase IV in the NHEJ pathway,in C. neoformans. We found that expression level of DNL4 was induced in response to DNA damage stress and wasdependent on the Rad53-Bdr1 pathway. Both deletions of DNL4 and RAD51 rendered strains more susceptible toradiation than each mutant, indicating that HR and NHEJ play redundant roles in DNA damage response. In addition,DNL4 was also increased under H2O2or tBOOH treatment although its deletion did not affect resistance to them. Perturbation of DNL4 increased microevolution, suggesting its potential role in genetic stability. However, dnl4∆mutant exhibited WT-levels of hyphal growth production. Taken together, C. neoformans Dnl4 plays roles in DNAdamage response and microevolution.