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

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Fungal anticodon ribonucleases (ACNases) like PaT cause DNA damage by cleaving tRNA.
• Translational stress can impact cellular processes beyond protein synthesis.

Purpose of the Study:

• To investigate if other translational stressors induce DNA damage-like responses in yeast.
• To identify DNA repair pathways involved in mitigating the toxicity of translational inhibitors.
• To elucidate the role of specific DNA repair enzymes in response to translational stress.

Main Methods:

• Yeast genetics and mutant analysis.
• Assessing toxicity of translational inhibitors (zymocin, PaT, hygromycin B).
• Investigating DNA repair pathways (BER, HR, PRR, NHEJ) and specific enzyme functions (AP endonucleases, Ung1, Mag1, polymerase ζ).

Main Results:

• Translational antibiotics, including hygromycin B (HygB), zymocin, and PaT, induce DNA damage-like responses in yeast.
• Base excision repair (BER), homologous recombination (HR), and post-replication repair (PRR) pathways conferred protection against translational inhibitors.
• Non-homologous end-joining (NHEJ) exacerbated the toxicity of these inhibitors, while AP endonuclease activity was protective.
• Mutation frequencies increased upon exposure to ACNases and HygB, with polymerase ζ contributing to mutagenic effects.

Conclusions:

• Inhibitors of protein biosynthesis trigger conserved DNA damage responses in yeast.
• Genome stability is dependent on translational fidelity, as evidenced by the interplay between translation and DNA repair.
• Specific DNA repair mechanisms are crucial for tolerating DNA damage induced by translational stress.