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The functions and regulation of ubiquitin and ubiquitin-like modifications in responses to reactive oxygen species

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  • Full or part time
    Prof B Morgan
    Prof J Quinn
    Dr Niall Kenneth
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Cell damage caused by reactive oxygen species (ROS), generated by aerobic metabolism or exposure to environmental agents such as sunlight, is intimately linked with the development of common human diseases such as cancer, diabetes, neurodegenerative and cardiovascular diseases. However, ROS are also beneficial with low levels utilised as signalling molecules and high levels produced by the immune system to kill invading organisms, such as the pathogenic fungus Candida albicans. These different effects, depending on the levels or specific type of ROS, makes understanding how cells respond to ROS a challenging but rewarding area of biological research. Indeed, advances in this area are vital to develop effective clinical strategies to specifically target the “bad” influence of ROS in human health or improve treatments against fungal infections. Our work using the tractable evolutionarily divergent yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, and the major human fungal pathogen Candida albicans, has made major contributions to current understanding of eukaryotic ROS responses, identifying multiple new mechanisms by which cells respond to ROS. Excitingly, we and others have recently found that ROS responses involves the regulation of the attachment of highly conserved ubiquitin (Ub) and ubiquitin-like (Ubl) polypeptides to the lysine residues on protein substrates. Modification of proteins by Ub/Ubl polypeptides regulates many fundamental processes in eukaryotes such as the cell division cycle and responses to environmental stress. Importantly, deregulation of these modification pathways is also linked with common age-related diseases such as cancer and neurodegenerative disease, and to specific human viral and bacterial infections. However, despite these links and the identification of many Ub/Ubl substrates there is much to learn about how these protein modifications influence human health. Hence the project will build on our ground-breaking work, using the model systems S. cerevisiae and mammalian cells, together with C. albicans as a model pathogen. The aim of the project is to utilise a wide range of state-of-the-art techniques to provide fundamental insights into the mechanisms and functions of ROS sensing and response pathways through Ub/Ubl protein modification. The results of the project will contribute towards developing a comprehensive understanding of both the conserved and organism-specific molecular mechanisms by which eukaryotic cells sense and respond to different types and levels of ROS.

HOW TO APPLY

Applications should be made by emailing [Email Address Removed] with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to [Email Address Removed]

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs. (2018) mBio 9(2), e02229-17

Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis. (2018) Nature Communications, 9(1), 256

XIAP upregulates expression of HIF target genes by targeting HIF1α for Lys63-linked polyubiquitination. (2017) Nucleic Acids Research, 45(16), 9336-9347

Blocking two-component signalling enhances Candida albicans virulence and reveals adaptive mechanisms that counteract sustained SAPK activation. (2017) PLoS Pathogens, 13, e1006131

SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair. (2016) Autophagy, 12, 1917-1930

Mechanisms underlying the delayed activation of the Cap1 transcription factor in Candida albicans following combinatorial oxidative and cationic stress important for phagocytic potency. (2016) mBio, 7(2), e00331-16

A peroxiredoxin promotes H2O2 signaling and oxidative stress resistance by oxidizing a thioredoxin family protein. (2013) Cell Reports, 5, 1425-1435

Ybp1 and Gpx3 signaling in Candida albicans govern hydrogen peroxide-induced oxidation of the Cap1 transcription factor and macrophage escape. (2013) Antioxidants and Redox Signaling, 19, 2244-2260

Oxidative stress responses involve oxidation of a conserved ubiquitin pathway enzyme. (2012) Molecular and Cellular Biology, 32, 4472-4481

Inactivation of a peroxiredoxin by hydrogen peroxide is critical for thioredoxin-mediated repair of oxidized proteins and cell survival. (2012) Molecular Cell, 45, 398-408



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