|During the 5 past years, the team has studied the mechanisms controlling translation termination in mammalian cells and has evaluated the role of translation termination factors in the control of cell growth and proliferation. Our studies help to decipher the mechanism connecting translation termination efficiency, mTOR signaling pathway and the activation of activating transcription factor 4 (ATF4) which is a key player in stress response. For the next five years, we will take advantage of our knowledge on translation, mTOR signaling pathway and stress response to address questions on factors which function as translation and mRNA turnover regulatory elements throughout life from development to ageing. Our research projects will focus on:
1) The mechanisms which regulate gene expression at the translational level during cell differentiation and ageing. Gene expression patterns change dramatically depending on tissue, metabolic status, and age. The specific subsets of proteins expressed at each time point allow cells to carry out the functions needed during differentiation and in response to stress conditions. Our goal is to improve our knowledge on the role of translational control during the reprogramming of gene expression leading to differentiation and to evaluate the implication of ageing in this process.
2) The involvement of the translation termination process in mRNA degradation. The interaction between the release factor eRF3 and the poly(A) binding protein PABP is known for many years. However, the role of this interaction in mRNA degradation is poorly understood. Our project is to improve our understanding of the function of eRF3 in mRNA deadenylation and how these processes are integrated during environmental changes and ageing.
3) The mechanisms that counteract the cytotoxic effect of RNA damage. Most agents that damage nucleic acids affect DNA and RNA molecules equally. However, damaged RNA seems to cause cytotoxicity through the production of erroneous proteins during translation. Furthermore, data in the literature suggest that damaged RNA molecules may play a fundamental role in the development of age-associated neurodegeneration. Our project is to elucidate the mechanisms able to counteract the deleterious effects of RNA damage and to decipher the potential role of these mechanisms in the etiology of age related diseases.
The combination of investigations into the regulators of RNA translation and mechanisms for decreasing the toxicity of damaged RNA provide complementary studies to those of the Friguet/Rouis team to identify different mechanisms to reduce the deleterious effects of abnormal proteins in cells and thus addresses a key cellular abnormality associated with both normal and pathological ageing.