University of Dundee

MRC DTP 4 Year PhD Programme: Unravelling the phospho-code of the 26S proteasome under stress

Increasing evidence shows that alterations and mutations in the UPS give rise to various human diseases, such as cancer and neurodegenerative disorders. Our interest is to understand how the activity of the ubiquitin-proteasome system is regulated in cells so that accumulation of unfolded, misfolded, or damaged proteins can be cleared before they become deleterious (Rousseau and Bertolotti, 2018, Nature Reviews Molecular Cell Biology). We recently reported that proteasomal degradation is regulated upon proteotoxic stresses in a phosphorylation-dependent manner (Rousseau and Bertolotti, 2016, Nature). The new project will focus on how protein phosphorylation events regulate protein degradation and cell survival. Preliminary data in the lab from global phosphoproteomics upon proteotoxic stresses have identified several phosphosites present on diverse subunits of the 26S proteasome. The project will aim at identifying phosphorylation events which are essential for protein degradation by the 26S proteasome, especially upon proteotoxic stresses. The impact of these phosphorylation events on the degradation of unwanted protein such as damaged and misfolded proteins will be further tested. Another important aspect will be to identify the kinases responsible for proteasome phosphorylation. Both yeast and mammalian systems will be used for this project. Understanding how proteasomal degradation is regulated will help identifying new strategies to either increase or decrease the rate of protein degradation in cells. Interfering with proteasomal degradation could be beneficial to treat cancers while improving protein degradation capacity might be useful to treat diseases associated with protein misfolding and aggregation.

This project will allow the candidate to learn a broad range of techniques including yeast genetics, biochemistry, proteomics and molecular and cellular biology.

References

Adrien Rousseau and Anne Bertolotti. Regulation of proteasome assembly and activity in health and disease. Nature Reviews Molecular Cell Biology (2018),

DOI: 10.1038/s41580-018-0040-z

Adrien Rousseau and Anne Bertolotti. An evolutionarily conserved pathway controls proteasome homeostasis. Nature (2016), Nature 536, 184–189

Eligibility