(WIS) Deciphering the ribosome code and its role in translational control

Protein concentration within the cell is regulated not only at the transcriptional and post-translational levels, but also at the level of translation itself. Typically, ribosomes are considered as an invariant driving force behind protein expression, however, recent work suggests that they add an important, if not critical, layer of regulatory control that defines the subsets of mRNAs that are translated and to what extent and purpose. Moreover, these studies imply that ribosome composition can also be regulated in order to create specialized ribosomes conducive to the recognition and translation of specific mRNAs and mRNA subsets. Thus, ribosome heterogeneity, in terms of the incorporation of different ribosomal proteins (RPs), RP paralogs, ribosome-associated proteins or binding factors (RBFs), or rRNAs into assembling ribosomes may directly control both mRNA translation and the translatome. Yet, very little is known of the full extent of ribosome heterogeneity within cells, how it is created, and how it is controlled in order to regulate the physiology of eukaryotic cells.

This proposed joint program builds upon our breakthroughs which show that the incorporation of specific RP paralogs in yeast greatly alters their ability to confer normal cellular responsiveness to stress and the identification of mRNAs specifically translated by specialized ribosomes, as well as RBFs that associate with functional ribosomes. So far, the results imply that ribosomes specialized for the translation of specific mRNA subsets are generated by incorporating specific RP paralogs and RBFs. Yet due to RP gene duplication and the large number of RBFs, we have little idea of the full extent of ribosome heterogeneity that actually exists within cells, how it is created, and whether it ultimately controls the proteome. This joint synergistic program will engage these different questions and shed light on the importance of ribosome specialization by using a simple genetic model combined with modern molecular biology and proteomic experimental approaches. A further goal is to extrapolate these findings to future studies with mammalian cells.

https://www.research.manchester.ac.uk/portal/graham.pavitt.html


Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.