TRNA DYNAMICS

tRNA homeostasis and gene regulation

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 Obiettivo del progetto (Objective)

'Regulation of gene expression is a fundamental process in all cellular systems. While the major steps in gene regulation such as transcription and translation are well understood, the role of tRNA availability (e.g. abundance, half-life) in regulating translation is largely unknown. The ultimate objective of this proposal is to investigate how tRNA availability within a cell can influence which mRNA molecules are actively translated by the ribosome. More specifically, it aims to address (i) whether mechanisms such as transcription, nucleo-cytoplasmic transport and degradation vary for individual tRNAs coding for different amino acids and (ii) how altered tRNA dynamics can affect protein abundance, and hence fitness, in different cellular conditions. To address these questions, I propose systematically charting the tRNA abundance landscape using yeast as a model organism. I will quantitatively investigate the processes of tRNA production, transport and degradation, in order to determine which steps in tRNA homeostasis are altered under diverse stress conditions, compared to optimal growth conditions. I will then investigate the impact of tRNA dynamics in cell fitness through competitive growth experiments. In this manner, I propose to construct the first dynamic map of tRNA abundance, which holds the potential to help understand the process of gene expression regulation in fine detail. In the long-term, the goals described in this proposal will not only provide new insights into regulatory mechanisms of protein translation but will also help to achieve a better understanding of factors that influence fitness and cell survival. With recent discoveries relating changes in tRNA abundance to apoptosis and gene misregulation in tumorigenic cells, future research on understanding how tRNA availability is regulated and how it contributes to cell survival could lead to new strategies for the rational design of molecular therapies against cancer.'

Introduzione (Teaser)

Recent discoveries relate changes in transfer RNA (tRNA) abundance to apoptosis and gene misregulation in tumourigenic cells. A European study investigated the processes affecting tRNA abundance under stress.

Descrizione progetto (Article)

tRNA is a necessary component of protein synthesis. It transfers an amino acid to a growing polypeptide chain during translation. Recent reports show that the abundance of the total tRNA pool can vary during the cell cycle. Demonstrating that the tRNA pool in the cell is adaptable will add a new regulatory level with important implications for cell biology.

The EU-funded TRNA DYNAMICS (tRNA homeostasis and gene regulation) project studied tRNA abundance in yeast as a model organism. The project quantitatively studied tRNA homeostasis, which was altered under diverse stress conditions. The project investigated whether transcription, nucleo-cytoplasmic transport and degradation varied for individual tRNAs coding for different amino acids. The effects of altered tRNA dynamics on protein abundance and cell fitness were assessed under different cellular conditions.

Results showed that individual tRNAs changed under stress conditions in yeast in a time-dependent manner. During stress, the changes were mostly related to tRNA degradation. A stress-related ribonuclease was identified as a key player in the specific regulation of tRNAs. Scientists also found that tRNA abundance was affected by tRNA shuttling between nucleus and cytoplasm. The active shuttling occurred during stress and was dependent on the stress condition. The changes in tRNA abundance impacted protein synthesis and thus can be considered a new regulatory layer in the cell.

TRNA DYNAMICS results support the concept that tRNA abundance is tightly controlled in the cell and regulates protein synthesis in the ribosome. Better understanding of tRNA availability regulation and its connection to cell survival could potentially empower the design of new molecular therapies for cancer.