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  How does SUMOylation regulate cell survival and death in Heat Shock Response?


   School of Biosciences

   Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Heat shock response (HSR) is a universally existing essential phenomenon for all living organisms to survive sudden increases in environmental temperature that have pronounced damaging effects on important cellular structures and functions (1). Importantly, HSR is established as a paradigmatic model system for studying ageing (2), ‘protein conformational diseases’ (including neurodegeneration and viral infection, where accumulated misfolded proteins lead to cell death) (3), and for studying the mechanisms underlying hyperthermia-based cancer therapy (4). It is known that a marked increase in global SUMOylation as part of the HSR counteracts heat shock (HS)-induced cell death to promote cell survival (5). However, it is unclear how SUMOylation regulates cell survival and death after HS. Drawing on our expertise in the biology of SUMO cellular stress responses (6-10), in this project we will identify key SUMO targets and their regulators in HSR and elucidate their mechanistic role in cell fate decisions. The findings from this project could lead to the establishment of new tractable approaches to treat ‘protein conformational diseases’ and improve hyperthermia-based cancer treatments. The proposed work will involve a combination of techniques, including those in molecular biology (e.g., cloning and tagging and site-directed mutagenesis), protein chemistry (e.g., glutathione S-transferase/Histidine pulldowns & co-immunoprecipitations followed by western blotting, protein purification and assays for SUMOylation/deSUMOyation), cell biology (e.g., cultures of clonal cell lines, neuronal and cancerous cells, and DNA & sh/siRNA transfections/CRISPR-Cas9-mediated knockdown/knockout and replacement) together with proteomics and microscopy imaging analysis within our state of the art facilities (https://www.sheffield.ac.uk/mass-spectrometry; https://www.sheffield.ac.uk/lmf) as well as biochemical assays of cell survival and death under different experimental conditions.

Science Graduate School

As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more.

Biological Sciences (4) Medicine (26)

Funding Notes

This position is for self funded or externally funded students only.
First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University's application form using the following link: View Website
All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information.

References

1. R. Gomez-Pastor, E. T. Burchfiel, D. J. Thiele, Regulation of heat shock transcription factors and their roles in physiology and disease. Nature reviews. Molecular cell biology 19, 4-19 (2018).
2. M. A. Thompson, E. A. De-Souza, A Year at the Forefront of Proteostasis and Aging. Biology open 12, (2023).
3. Y. Miyazaki, L. C. Chen, B. W. Chu, T. Swigut, T. J. Wandless, Distinct transcriptional responses elicited by unfolded nuclear or cytoplasmic protein in mammalian cells. eLife 4, (2015).
4. J. Crezee, N. A. P. Franken, A. L. Oei, Hyperthermia-Based Anti-Cancer Treatments. Cancers 13, (2021).
5. F. Golebiowski et al., System-wide changes to SUMO modifications in response to heat shock. Sci Signal 2, ra24 (2009).
6. C. Guo et al., SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia. The EMBO journal 32, 1514-1528 (2013).
7. C. Guo, K. A. Wilkinson, A. J. Evans, P. P. Rubin, J. M. Henley, SENP3-mediated deSUMOylation of Drp1 facilitates interaction with Mff to promote cell death. Sci Rep 7, 43811 (2017).
8. C. Guo et al., SENP3 Promotes an Mff-Primed Bcl-x (L) -Drp1 Interaction Involved in Cell Death Following Ischemia. Frontiers in cell and developmental biology 9, 752260 (2021).
9. E. Waters et al., The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1. EMBO reports 23, e48754 (2022).
10. M. Zhang, A. Zhao, C. Guo, L. Guo, A combined modelling and experimental study of heat shock factor SUMOylation in response to heat shock. Journal of theoretical biology 530, 110877 (2021).
Website links:
https://www.sheffield.ac.uk/biosciences/people/academic-staff/chun-guo
https://scholar.google.co.uk/citations?user=ruFPXZAAAAAJ

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