title: DNA Damage Responses Are Induced by tRNA Anticodon Nucleases and Hygromycin B.
abstract: 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.
authors.affiliation: Institut für Molekulare Mikrobiologie und Biotechnologie, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Wemhoff
authors.affiliation: Institut für Biologie, Fachgebiet Mikrobiologie, Universität Kassel, Kassel, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Klassen
authors.affiliation: Institut für Molekulare Mikrobiologie und Biotechnologie, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Beetz
authors.affiliation: Institut für Molekulare Mikrobiologie und Biotechnologie, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Meinhardt
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004249:DNA Damage; D006921:Hygromycin B / Q000494:pharmacology*; D009154:Mutation; D014176:Protein Biosynthesis / Q000187:drug effects; D012331:RNA, Fungal / Q000235:genetics; D012343:RNA, Transfer / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism*; D015003:Yeasts / Q000201:enzymology / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
chemical_list: D012331:RNA, Fungal; D006921:Hygromycin B; D012343:RNA, Transfer; D012260:Ribonucleases; C049345:anticodon nuclease