Role of FXR proteins in the cell stress response

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The coordinated control of mRNA translation is fundamental for eukaryotic cell homeostasis, particularly in response to physiological and pathological stress. Alterations of this program can lead to the growth of damaged cells, a hallmark of cell transformation and cancer, or to premature cell death, such as observed in neurodegeneration and infertility. Fragile X-related proteins (FXRPs) are RNA-binding proteins that play a key role in mRNA translation and have a function that is associated with cell stress responses. However, the underlying mechanisms by which FXRPs regulate the mRNA translation that is required for a cell to cope with stress remains largely unknown.***Our recent investigations identified a novel role of FXRPs in the cellular response to UVC radiation, which occurs in part by promoting the formation of cytoplasmic RNA granules (UVCGs). FXRP-induced UVCGs are reminiscent of stress granules (SG); RNA foci known to sequester untranslated mRNAs upon stress and formation of which promotes cell survival under stress. As preliminary data, we found that FXRP-derived UVCGs promote UV-induced cell cycle arrest, a phenomenon that is required for the repair of UV-induced DNA damage and survival. Our hypothesis is that UVCGs induced by FXRPs contribute to cell cycle arrest upon UVC exposure by temporarily repressing the translation of mRNAs encoding cell cycle functions. The goal of this research program is therefore to define the mechanisms by which FXRPs promote the formation of UVCGs, leading to cell cycle arrest upon UVC exposure. To achieve this goal, we will address the following objectives: I- to demonstrate the role of FXRPs in UVCG formation; II- to investigate the mechanism(s) by which FXRPs promote UVCG formation; III- to demonstrate the role of FXRPs in UVC-induced cell cycle arrest through UVCG formation. For our studies, we will use mouse embryonic fibroblasts (MEFs) as well as human HeLa and PC3 cell lines, which efficiently form UVCGs. This will ensure that our results are not cell-type specific. For drosophila studies, we will use S2 cells as well as isolated tissues. By combining immunostaining, immunoprecipitation, knockdown experiments, FISH, polysome fractionation combined with RNA-Seq, we expect to establish FXRPs as key players in the regulation of the cell cycle and the associated cellular resistance to stress, potentially by promoting RNA granule formation.****Following these studies, future investigations will be designed to determine the contribution of this novel RNA granule-based mechanism in stress-related human disorders, including neurodegeneration and infertility. ***********