Misactivation of multiple starvation responses in yeast by loss of tRNA modifications

Previously, combined loss of specific anticodon loop modifications was shown to impair the function of distinct tRNAs in Saccharomyces cerevisiae. Surprisingly, each scenario resulted in shared cellular phenotypes, the basis of which is unclear. To investigate how loss of different tRNA modifications can induce overlapping phenotypes, we characterized global transcription patterns of modification mutants with defects in either tRNAGlnUUG or tRNALysUUU function. We observe that the mutants share an inappropriate induction of multiple starvation responses, including derepression of glucose and nitrogen catabolite-repressed genes as well as improper activation of amino acid biosynthesis and autophagy genes, all of which occur prematurely and inadequately in exponential growth phase. We further demonstrate that improper responses to starvation as well as the propensity of the tRNA modification mutants to form protein aggregates are diminished upon overexpression of tRNAGlnUUG or tRNALysUUU, the tRNA species that lack the modifications of interest. Hence, our data suggest that global alterations in mRNA translation and proteostasis (rather than codon specific defects in translation) account for the transcriptional stress signatures that are commonly triggered by loss of anticodon modifications in different tRNAs. Examination of 4 different yeast mutants compared to WT strain