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Efficient protein synthesis in eukaryotes requires diphthamide modification of translation elongation factor eEF2 and wobble uridine modifications of tRNAs. In higher eukaryotes, these processes are important for preventing neurological and developmental defects and cancer. In this study, we used  Schizosaccharomyces pombe  as a model to analyse mutants defective in eEF2 modification ( dph1Δ ), in tRNA modifications ( elp3Δ ), or both ( dph3Δ ) for sensitivity to cytotoxic agents and thermal stress. The  dph3Δ  and  elp3Δ  mutants were sensitive to a range of drugs and had growth defects at low temperature.  dph3Δ  was epistatic with  dph1Δ  for sensitivity to hydroxyurea and methyl methanesulfonate, and with  elp3Δ  for methyl methanesulfonate and growth at 16 °C. The  dph1Δ  and  dph3Δ  deletions rescued growth defects of  elp3Δ  in response to thiabendazole and at 37 °C. Elevated tRNA Lys   UUU  levels suppressed the  elp3Δ  phenotypes and some of the  dph3Δ  phenotypes, indicating that lack of tRNA Lys   UUU  modifications were responsible. Furthermore, we found positive genetic interactions of  elp3Δ  and  dph3Δ  with  sty1Δ  and  atf1Δ , indicating that Elp3/Dph3-dependent tRNA modifications are important for efficient biosynthesis of key factors required for accurate responses to cytotoxic stress conditions.

Elp3 and Dph3 of Schizosaccharomyces pombe mediate cellular stress responses through tRNALys UUU modifications