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

ABSTRACT: Previously, combined loss of different 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. Since loss of tRNA modification may evoke transcriptional responses, we characterized global transcription patterns of modification mutants with defects in either tRNAGlnUUG or tRNALysUUU function. We observe that the mutants share inappropriate induction of multiple starvation responses in exponential growth phase, including derepression of glucose and nitrogen catabolite-repressed genes. In addition, autophagy is prematurely and inadequately activated in the mutants. We further demonstrate that improper induction of individual starvation genes 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 account for the transcriptional stress signatures that are commonly triggered by loss of anticodon modifications in different tRNAs.

SUBMITTER: Bruch A

PROVIDER: S-EPMC7367188 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Bruch Alexander A Laguna Teresa T Butter Falk F Schaffrath Raffael R Klassen Roland R

Nucleic acids research 20200701 13

Previously, combined loss of different 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. Since loss of tRNA modification may evoke transcriptional responses, we characterized global transcription patterns of modification mutants with defects in either tRNAGlnUUG or tRNALysUUU function. We observe that the mutants share inappropriate inducti ...[more]

PMID: 32484543

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Project description:Modified nucleotides are prevalent in tRNA. Experimental studies reveal that these covalent modifications play an important role in tuning tRNA function. In this study, molecular dynamics (MD) simulations were used to investigate how modifications alter tRNA dynamics. The X-ray crystal structures of tRNA(Asp), tRNA(Phe), and tRNA(iMet), both with and without modifications, were used as initial structures for 333 ns explicit solvent MD simulations with AMBER. For each tRNA molecule, three independent trajectory calculations were performed, giving an aggregate of 6 μs of total MD across six molecules. The global root-mean-square deviations (RMSD) of atomic positions show that modifications only introduce significant rigidity to the global structure of tRNA(Phe). Interestingly, RMSDs of the anticodon stem-loop (ASL) suggest that modified tRNA has a more rigid structure compared to the unmodified tRNA in this domain. The anticodon RMSDs of the modified tRNAs, however, are higher than those of corresponding unmodified tRNAs. These findings suggest that the rigidity of the anticodon stem-loop is finely tuned by modifications, where rigidity in the anticodon arm is essential for tRNA translocation in the ribosome, and flexibility of the anticodon is important for codon recognition. Sugar pucker and water residence time of pseudouridines in modified tRNAs and corresponding uridines in unmodified tRNAs were assessed, and the results reinforce that pseudouridine favors the 3'-endo conformation and has a higher tendency to interact with water. Principal component analysis (PCA) was used to examine correlated motions in tRNA. Additionally, covariance overlaps of PCAs were compared for trajectories of the same molecule and between trajectories of modified and unmodified tRNAs. The comparison suggests that modifications alter the correlated motions. For the anticodon bases, the extent of stacking was compared between modified and unmodified molecules, and only unmodified tRNA(Asp) has significantly higher percentage of stacking time. Overall, the simulations reveal that the effect of covalent modification on tRNA dynamics is not simple, with modifications increasing flexibility in some regions of the structure and increasing rigidity in other regions.

Dataset Information

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

Publications

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

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