Thursday, April 18, 2024
4/18/2024
Project Summary Protein synthesis is a core function of all cells and is the target of multiple signaling pathways that coordinate the translation of mRNAs into proteins in response to exogenous and internal signals. Work from this and other laboratories has highlighted that cyclical signals from the light environment, temperature, metabolic biomarkers, and the circadian clock are integrated to coordinate mRNA ribosome loading on a genome-wide scale. Central in this network is the signaling axis known as the TOR-S6 kinase pathway. It regulates the phosphorylation of several components of the cytosolic translation apparatus including one prominent target on the ribosome, the eS6 protein located at the foot of the small ribosomal subunit. The model system underlying the current project, Arabidopsis thaliana, is not only representative of higher eukaryotes because of the conservation of its TOR-S6K-eS6 signaling channel, but is also an ideal system to study the integration of various cyclical signals in a chronobiological context. The first aim of the project builds on innovative and established molecular, biochemical, and cellular assays to tackle a long-standing question, the biochemical and cellular role of eS6-phosphorylation. Plants in which phosphorylation of eS6 is abolished or otherwise disrupted display at most minor defects in their growth, development, and transcriptome. Therefore, detailed assays of translational fidelity, ribosome biogenesis, translation, and autophagy will be refined and applied to identify the biochemical and cellular scope of eS6 phosphorylation. The second aim is a collaboration with a group of versatile computational biologists under co-investigator Tian Hong. As the cell processes multiple independent circadian signals, it can be predicted theoretically that the precise mode of their integration will lead to new circuit properties including complex waveforms or even ultradian periods. The project will use bioinformatic data mining, mathematical modeling, and wet-lab experimentation to distinguish between competing hypotheses to explain how multiple cyclical signals are integrated with each other.
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