Translational control by RNA-binding proteins in response to nutritional stress

Protein synthesis is a central activity of all cells and is a highly regulated process within the gene expression pathway. Proteins that bind to both specific mRNAs and to ribosomes are central partners in networks mediating translational control. The protein FMRP is one example, when mutated or deleted this causes the disorder Fragile X Syndrome.
For most RNA-binding proteins (RBPs) very little is understood about how they choose their mRNA targets and how they exert control. We have been using modern 'omics' techniques, combined with bioinformatics and 'classical' molecular biology/biochemistry to study how several translation factors and RBPs respond to cellular stress using the eukaryote Saccharomyces cerevisiae as a tractable model system. We have begun to uncover global mechanisms of action of specific repressors and activators of translation: proteins that interact both with mRNAs and with ribosomes. This suggests novel modes of action with more specificity in protein-mediated control of mRNA translation than previously expected. This project will build upon our earlier studies to uncover novel regulatory mechanisms mediating translational control. As recombinant proteins are used therapeutically and in industry, we will assess the ability to transfer translational control elements to test RNAs to maximise recombinant protein expression.

References:
Castelli LM Talavera D, Mohammad-Qureshi SS, Kershaw CJ, Costello JL, Rowe W, Sims PF, Ashe MP, Grant CM, Hubbard SJ, and Pavitt GD (2015). The 4E-BP Caf20p mediates both eIF4E-dependent and independent repression of translation. PLOS Genetics 11:e1005233
Costello JL, Rowe W, Castelli LM, Kershaw CJ, Talavera D, Sims PF, Grant CM, Pavitt GD, Hubbard SJ and Ashe MP (2015) Global mRNA selection mechanisms for translation initiation. Genome Biology 16 (1), 10.
Kershaw CJ Costello JL, Castelli LM, Talavera D, Rowe W, Sims PF, Ashe MP, Hubbard SJ, Pavitt GD and Grant CM (2015) The yeast La Related Protein Slf1p is a Key Activator of Translation During the Oxidative Stress Response. PLOS Genetics 11(1):e1004903.
Rowe W, Castelli LM, Kershaw CJ, Costello JL, Ashe MP, Grant CM, Sims PF, Pavitt GD and Hubbard SJ (2014) Puf3p induces translational repression in response to oxidative stress. Nucleic Acids Research 42:1026-41
Jennings MD, Zhou Y, Mohammad-Qureshi SS, Bennett D, and Pavitt GD. (2013). eIF2B promotes eIF5 dissociation from eIF2 GDP to facilitate guanine nucleotide exchange for translation initiation. Genes Dev, 27(24), 2696-2707.