Reference : PhD Bertrand Séraphin
The regulation of gene expression is particularly complex in eukaryotic organisms. This essential process allows cells to adapt to changing conditions and / or differentiate. This control occurs mainly by changes in transcription or degradation of messenger RNA that allow the synthesis in greater or lesser quantities of proteins needed by cells.
Our work on the degradation of messenger RNAs enabled us to characterize several protein complexes involved in a critical step of this process. Among them, the CCR4-NOT complex is a large assembly that regulates eukaryotic gene expression at multiple levels. It has been implicated in a large range of molecular functions such as mRNA deadenylation, translation repression, protein ubiquitylation… This large assembly is composed of a core conserved across all eukaryotic organism examined to date associated with species or phyla specific subunits. The best-studied function of CCR4–NOT relates to its catalytic role as the major deadenylase involved in shortening the poly(A) tail of cellular mRNAs in the cytoplasm. Deadenylation by CCR4–NOT is indeed a key step in the constitutive and regulated turnover of mRNAs. Understanding the biological role of the CCR4–NOT complex in deadenylation and the regulation of this process entails determining the organization of the complex, the role of individual subunits and identification of interacting partner modulating its activity.
Our preliminary data provide new insights into the organization of the CCR4-NOT complex and identify new partners of this essential cellular assembly. Based on this information, the biological role of these interactions will be investigated through in in vivo analyses (characterization of mutants, analyses of reporter genes...) and biochemical assays (activity tests, protein-protein interaction studies...). This project will provide a molecular and functional understanding of the CCR4-NOT complex and of its role at the interface of degradation of messenger RNA, translation and protein stability. In particular, the involvement of such a process in quality control mechanisms eliminating faulty mRNAs will also be explored. These analyses will provide information to explain the physiological role of the CCR4-NOT complex including its impact on development and diseases such as cancer.
Application Deadline : Nov. 1, 2018