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Interplay between the translation of upstream open reading frames and ribosome nascent chain-associated factors to control gene expression in eukaryotic cells


Project Description

Eukaryotic mRNAs typically contain one open reading frame that is translated into protein. However many mRNAs contain additional upstream ORFs (uORFs) that regulate protein expression by controlling the flow of ribosomes to the main ORF, often by regulated reinitiation. In human cells, up to 50% of mRNAs have been shown to possess uORFs indicating this is a major mechanism to regulate gene expression. Studies suggest that uORFs that permit reinitiation downstream typically encode short (<30-35 amino acids) polypeptides.

During translation, enzymes associate with the ribosome near the polypeptide exit tunnel to modify the amino-terminus of the emerging peptide chain. These modifications impact on the fate of the newly synthesized protein. Because short uORFs terminate translation before the nascent chain has emerged from the ribosomal polypeptide exit tunnel, they are not thought to be modified by the nascent chain-associated factors. The fate of longer uORFs and their interactions with ribosome-associated proteins has not been investigated.

The relationship between reinitiation of translation and ribosome-associated protein modifying enzymes has not previously been studied. Building upon the combined expertise of the Pool and Pavitt labs this project will examine this relationship to determine rules that govern the ability of reinitiation of translation. Initially this project will make use of the large range of resources available to study these processes in the yeast Saccharomyces cerevisiae. However there may be scope to expand into mammalian cells.

The ability to co-express different genes from the same promoter has potential biotechnology uses and depending on the outcomes of the studies biotechnological applications could be exploited during the project.

This project will blend modern precision molecular biology techniques with biochemistry and yeast genetics.

As with all projects at this level the project will provide project, research and time management skills training as well as training in research presentation skills.

Candidates are expected to have, or about to obtain, an upper second class (or equivalent) undergraduate degree in molecular biology, biochemistry or a related subject area. A Masters qualification in a similar area and/or prior practical experience with independent laboratory work would be a distinct advantage.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website). Informal enquiries may be made directly to the primary supervisor.

References

1. Dever TE, Goss-Kinzy T, Pavitt GD (2016) Mechanism and regulation of protein synthesis in Saccharomyces cerevisiae. Genetics ‘Yeastbook’ series 203:65-107
2. Jennings MD, Kershaw CJ, White C, Burgess D, Costello JC, Richardson JP, Donaldson IJ, Zhou Y, Pavitt GD (2016). eIF2β is critical for eIF5-mediated GDP-dissociation inhibitor activity and translational control. Nucleic Acids Res online July 2016. PMID: 27458202. DOI: 10.1093/nar/gkw657.
3. Nyathi Y & Pool MR (2015) Analysis of the interplay of protein biogenesis factors at the ribosome exit site reveals new role for NAC. J. Cell Biol. 210: 287-302
4. Forte GMA, Pool MR & Stirling CJ (2011) N-terminal acetylation inhibits protein targeting to the endoplasmic reticulum. PLoS Biol. 9:e1001073.

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