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Click here to search FindAPhD.com for PhD studentship opportunities(BBSRC DTP) Understanding how translation elongation regulates protein synthesis in the response to oxidative stress
About the Project
All aerobic organisms are exposed to reactive oxygen species (ROS) during normal aerobic metabolism or following exposure to radical-generating compounds. ROS can cause wide-ranging damage to cells and an oxidative stress is said to occur when the cellular survival mechanisms are unable to cope with the ROS or the damage caused by them. Oxidative damage is associated with various disease processes including cancer, ageing and neurodegenerative disorders and it is also of particular concern to industry including biotech, brewing and baking. This means that understanding the causes and molecular responses to oxidative stress is of broad fundamental importance. The specific focus of this project is to determine the role of translation in regulating gene expression during the response oxidative stress conditions, using the yeast Saccharomyces cerevisiae as a model organism.
Global inhibition of protein synthesis is a common response to stress conditions that serves to dampen this highly energy requiring process during times of stress. The main target of regulation has long been thought to be translation initiation. However, much recent data indicates that oxidative stress inhibits protein synthesis by additional mechanisms including inhibiting translation elongation. Attenuating elongating ribosomes in response to stress conditions, as opposed to ribosomal initiation, offers the advantage that ribosomes remain bound to mRNAs and can rapidly resume protein synthesis once the stress is removed or detoxified. For an oxidative stress condition, it would also prevent continued protein synthesis during potentially error-prone conditions. This is important since it is increasingly recognised that differential control of specific mRNAs is required for survival during growth under stress conditions. The major goal of this project is to therefore understand how protein synthesis is regulated in response to oxidative stress conditions, using cutting edge technology to examine the control of translation elongation. We have preliminary evidence supporting a regulatory role for the evolutionarily conserved eEF1 translation elongation factor complex in regulating the translational response to oxidative stress. This project aims to provide a mechanistic understand of how eEF1 controls protein synthesis which is important since its dysregulation has been implicated in many disease processes and ageing.
Eligibility
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/bbsrc-dtp/
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
Funding Notes
References
2. Cunningham, J., Sfakianosa, A.P., Kritsiligkoub, P, Kershaw C.J., Whitmarsh, A.J., Hubbard, S.J., Ashe, M.P. and Grant, C.M. (2023). Paralogous translation factors target distinct mRNAs to differentially regulate tolerance to oxidative stress in yeast. Nucleic Acids Res. 51: 8820-8835.
3. Jennings, M.D., Srivastava, P., Kershaw, C.J., Talavera, D., Grant, C.M. and Pavitt, G.D. (2023) Interaction of the Larelated protein Slf1 with colliding ribosomes maintains translation of oxidative-stress responsive mRNAs. Nucleic Acids Res 51:5755-5773
4. Kershaw, C.J., Nelson, M.G., Lui, L., Bates, C.P., Jennings, M.D., Hubbard, S.J., Ashe, M.P. and Grant, C.M. (2021)
Integrated multi-omics reveals common properties underlying stress granule and P-body formation. RNA Biology. 18: 655-673.
5. Crawford RA, Ashe, M.P., Hubbard SJ, Pavitt GD (2022). Cytosolic aspartate aminotransferase moonlights as a ribosome-binding modulator of Gcn2 activity during oxidative stress.. Elife. 11: e73466
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