Journal Article

DNA Damage Responses Are Induced by tRNA Anticodon Nucleases and Hygromycin B

Wemhoff, Sabrina, Meinhardt, Friedhelm, Klassen, Roland, Beetz, Anja

2016

Overview

Previous studies revealed DNA damage to occur during the toxic action of PaT, a fungal anticodon ribonuclease (ACNase) targeting the translation machinery via tRNA cleavage. Here, we demonstrate that other translational stressors induce DNA damage-like responses in yeast as well: not only zymocin, another ACNase from the dairy yeast Kluyveromyces lactis, but also translational antibiotics, most pronouncedly hygromycin B (HygB). Specifically, DNA repair mechanisms BER (base excision repair), HR (homologous recombination) and PRR (post replication repair) provided protection, whereas NHEJ (non-homologous end-joining) aggravated toxicity of all translational inhibitors. Analysis of specific BER mutants disclosed a strong HygB, zymocin and PaT protective effect of the endonucleases acting on apurinic sites. In cells defective in AP endonucleases, inactivation of the DNA glycosylase Ung1 increased tolerance to ACNases and HygB. In addition, Mag1 specifically contributes to the repair of DNA lesions caused by HygB. Consistent with DNA damage provoked by translation inhibitors, mutation frequencies were elevated upon exposure to both fungal ACNases and HygB. Since polymerase ζ contributed to toxicity in all instances, error-prone lesion-bypass probably accounts for the mutagenic effects. The finding that differently acting inhibitors of protein biosynthesis induce alike cellular responses in DNA repair mutants is novel and suggests the dependency of genome stability on translational fidelity.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aminoglycosides / Analysis / Antibiotics / Apurinic sites / Baking yeast / Base excision repair / Biology and Life Sciences / Biosynthesis / Cell cycle / Cell Cycle Checkpoints - drug effects / Damage / Deactivation / Deoxyribonucleic acid / DNA / DNA Damage / DNA glycosylase / DNA repair / Fungi / Genes / Genetic aspects / Genomes / Homologous recombination / Homology / Hygromycin / Hygromycin B / Hygromycin B - pharmacology / Inactivation / Inhibitors / Kluyveromyces lactis / Lesions / Medicine and Health Sciences / Mutagenesis / Mutants / Mutation / Non-homologous end joining / Nuclease / Physiological aspects / Pichia / Plasmids / Protein biosynthesis / Protein Biosynthesis - drug effects / Repair / Research and Analysis Methods / Ribonucleases - metabolism / Ribonucleotide reductase / RNA, Fungal - genetics / RNA, Transfer - metabolism / Saccharomyces cerevisiae / Toxicity / Toxins / Transfer RNA / Translation / tRNA / Yeast / Yeasts - enzymology / Yeasts - genetics / Yeasts - growth & development / Yeasts - metabolism