Primary Supervisor: Dr Mark Coldwell (University of Southampton)
Co-Supervisor: Prof Simon Morley (University of Sussex)
Co-Supervisor: Dr Jonathan West (University of Southampton)
During eukaryotic ribosome recruitment to the mRNA, the axis of eIF4E (m7G cap-binding):eIF4G (scaffold):eIF3(ribosome recruitment) is considered the canonical complex required for translation initiation. Preventing the interaction of eIF4E with eIF4G via competitive binding of 4E-BPs was thought to be the sole way of regulating formation of this complex. However, recent work suggest that there is much more fluidity in how interactions may “hand-off” parts of the process to each other. Based on “SLiMPrints” predictions, work from MJC has confirmed new interactions of eIF4E with eIF2A and eIF3g in alternate subcomplexes, while the helicase DDX3X (studied by the SJM group ) was independently verified as a further interacting partner of eIF4E. We propose to unite these studies into a PhD project to fully investigate how different novel partners of eIF4E regulate specific translation events, as our unpublished investigations suggest that eIF3g:eIF4E interaction is involved in cell cycle progression.
We will use Promega NanoBiT assay-based approaches developed by MJC for the eIF3g:eIF4E interaction to confirm interactions with other predicted novel partners. This can show direct intracellular interactions not easily studied by co-immunoprecipitation or similar methodologies. Mutating residues in eIF3g responsible for binding eIF4E leads to a reduction in cell proliferation, and delays progression through S-phase. We are currently working to identify the mRNAs that are differentially polysome associated in wildtype versus eIF4E:eIF3g binding-mutant cells to identify the genes responsible. This will present a novel area of research for the student to pursue at the outset of the project, while concomitantly elucidating the details of the other novel partners.
High throughput approaches to studying mRNA translation developed in recent years has shown that much of gene expression is controlled at the level of translation initiation with subsets of mRNAs under specific control. This work will expand our knowledge in understanding the rules of life.