B04: Chronic stress-associated alterations of translation fidelity

Translation is a multicomponent process and its fidelity strongly depends on the concentration of the translation constituents (e.g. ribosomes, mRNAs, tRNAs, translation factors) and mRNA-specific initiation and elongation rates. Acute stress quickly shuts down translation by inhibiting translation initiation and triggering stress-response cascades that decrease the active ‘translationally-competent’ concentration of the translation components with no discernible effect on their total concentration. Yet, it remains elusive whether similar alterations in the active concentration of translation components occur with long-lasting chronic stress and how chronic stress alters translation fidelity. Chronic stress requires proteome reprogramming, yet the effect on the concentration of translation components remains elusive. Our aim is to address the long-standing question in the field as to whether the concentrations of the translation components change with chronic exposure to oxidative stress, and how this influences translation fidelity and proteome composition and folding. We will perform a quantitative inventory of the translation machinery. In combination with transcriptome profiling, we will assess the dosage effect on gene expression and disentangle it from the transcriptional effects. We will use a malleable system, the HEK293 cell model to validate the model predictions. Some cell types, e.g. neuronal populations of the brain tissue, are more vulnerable to stress. We reason that it is because of the much lower relative to the cell size concentration of the translational constituents. Thus, we will quantify the translation pools of three different neuronal populations from murine brain tissues exposed to chronic oxidative stress and monitor the effects along the organismal life span. The proposal will be executed in a tight collaboration and relies on the distinct complementary expertise of both PIs: experimental data will be generated in Ignatova group and computational quantification and modelling in Tresch group.