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MRC DiMeN Doctoral Training Partnership: Mechanism of replication proofreading by SARS-CoV-2.


MRC DiMeN Doctoral Training Partnership

Newcastle United Kingdom Biochemistry Molecular Biology Structural Biology Virology

About the Project

The stubborn recurrence of coronaviral epidemics (we are now living through the third and deadliest outbreak of the 21st century) implies that we will face a new coronavirus soon. Vaccine efficacy and period of post-infection immunity are both still uncertain. The reliable way to treat existing and newly emerging coronaviruses infections is to use drugs targeting viral replication. Those drugs are substrate analogues which jam replication and transcription of the viral genome by RNA-dependent RNA polymerase, RdRp. Replication and transcription are central processes for viral propagation. The active site of RdRp is conserved among coronaviruses, therefore there would be drugs nearly universal against existing members of coronaviral family and those yet to evolve. 

However, coronaviruses present a unique challenge for this type of therapy since they possess dedicated proofreading mechanism. This mechanism recognises and removes incorrectly incorporated substrates, as well as antiviral drugs, causing therapy failures. However there are harder-to-detect chemical compounds that can have improved efficacy as drugs. How they are discriminated by RdRp, proofreading nuclease or, potentially, other viral proteins, is unclear. 

The overarching aim of the project is to investigate SARS-CoV-2 correction of mistakes in RNA synthesis at a molecular level. We will employ variety of biochemical and molecular biology techniques (protein expression and purification, footprinting assays, inhibition assays, RNA-protein crosslinking etc). Biochemical analysis will be supported by structural analysis of protein-RNA-substrates/inhibitors complexes to elucidate RdRP’s specificity, inhibition and proofreading mechanisms at atomic level. 

Our research has a potential to inform future drug design, improve drug screening assays by including a proofreading step, and further structural analysis of complex SARS-CoV-2 replication multi-protein complexes. Knowledge of error correction efficiency will help to model infection process, predict the upper limit of mutations virus can tolerate and therefore the speed of its evolution under different selective pressures/treatment regimes.

Primary supervisor, Yulia Yuzenkova’s group investigates gene expression in a range of organisms and viruses: https://www.ncl.ac.uk/cbcb/staff/profile/yuliayuzenkova.html#background. Second supervisor, Paula Salgado’s group works on structural analysis of proteins involved in pathogenesis and diseases: https://www.ncl.ac.uk/cbcb/staff/profile/paulasalgado.html#background. The supervisors’ Institute has a large proteomics and crystallographic facilities, including the UK's first liquid metal jet X-ray generator dedicated for single crystal diffraction experiments, as well as robotised High Throughput Screening Facility, which can be accommodated for various high throughput experiments, including genetic and drug screens.   

The PhD project will be based in a Centre for Bacterial Cell Biology, new building with modern equipment and nice scientific collaborative atmosphere: https://www.ncl.ac.uk/cbcb/. In the course of a PhD, student will have an opportunity to improve communication skills by presenting their research regularly on a conference-like seminars in the Centre, and getting efficient friendly feedback. Group’s PhD students communicate their research to wider public at various events, such as recent exhibition in Hancock Museum: https://portabolomics.ico2s.org/peals-20th-anniversary-exhibition-great-north-museum/

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

https://bit.ly/3lQXR8A 


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

Forrest D, James K, Yuzenkova Y, Zenkin N (2017) Single-peptide DNA-dependent RNA polymerase homologous to multi-subunit RNA polymerase. Nat Commun. 8:15774
Mosaei H et al. (2018) Mode of action of Kanglemycin A, an ansamycin natural product that is active against Rifampicin-resistant Mycobacterium tuberculosis. Mol Cell. 18;72(2):263-274
Salgado P, Koivunen M, Makeyev E, Bamford D, Stuart D, Grimes J (2006) The structure of an RNAi polymerase links RNA silencing and transcription. PLoS Biol 4(12):e434

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