MRC DTP 4 Year PhD Programme: Dealing with proteotoxic stress: How do cells tidy up when trash piles up?

This project is part of our exciting and challenging University of Dundee 4-year MRC DTP Programme in Quantitative and Interdisciplinary approaches to biomedical science. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science. Further information on the programme structure and training can be found at https://www.dundee.ac.uk/study/pg/phds/dtp/mrc-dtp/

This project is part of our exciting and challenging University of Dundee 4-year MRC DTP Programme in Quantitative and Interdisciplinary approaches to biomedical science. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science. Further information on the programme structure and training can be found at https://www.dundee.ac.uk/study/pg/phds/dtp/mrc-dtp/

Degrading proteins in a timely manner to dispose of misfolded and damaged proteins is essential for a healthy cell. In ageing cells and organisms, there is a deterioration in the ability of cells to clear proteins resulting in the accumulation of misfolded proteins. Deposition of misfolded protein aggregates is a hallmark of many neurodegenerative diseases. It is not understood why quality control systems and the degradation capacity of a cell decline with age. A better understanding of how cells cope with proteotoxic stress, the pathways and mechanisms involved and why these fail will not only advance our understanding of devastating diseases caused by misfolded proteins but also enable us to develop strategies to prevent disease and promote healthy ageing.

A central step in the degradation of misfolded proteins is their recognition by quality control systems and the addition of ubiquitin and ubiquitin-like-modifiers (Ubls) to mark misfolded proteins for degradation. The aims of this project are to study the enzymes that work together with protein quality control factors to attach ubiquitin and Ubls to misfolded proteins. In this project, you will build on recent exciting findings in the lab that have identified an E3 ligase that is important for the cellular response to proteotoxic stress. Using powerful reconstitution approaches, biochemistry and state-of-the-art proteomics you will determine the underlying molecular mechanisms.