Training Opportunity: This project will appeal to a motivated student who wants experience and training in both an academic setting, and in the world-class research labs of a leading biotechnology company. In this joint academic-industrial proposal between Durham University and New England Biolabs, the student will gain skills in a range of techniques including molecular biology, microbiology, protein biochemistry, structural biology and next generation sequencing. The topic offers an exciting program of work in a rapidly developing field, with excellent job prospects. As this is a CASE studentship, the student will be based at Durham University, with a placement at New England Biolabs.
Background: Bacteriophages (phages) outnumber bacteria by ten to one, and the selection pressure has led to the evolution of phage-resistance systems that protect bacteria from phage predation. Many of these systems have proved invaluable to biochemists: restriction-modification and CRISPR-cas underpin the recombinant DNA and genome editing revolutions. This project will investigate the continuing attack and counter-attack between phage and bacteria.
We have recently characterised BrxU, a highly promiscuous restriction enzyme that recognises multiple different DNA modifications, and uses any nucleotide, together with a wide selection of metals, to cleave modified DNA (https://doi.org/10.1093/nar/gkab906). How these ligands are used, and how modification recognition leads to cleavage, remains to be uncovered. Furthermore, phages have evolved protein inhibitors of the BrxU family and exploring these interactions will allow further understanding of the BrxU mechanism. Beyond this fundamental biochemistry, the BrxU enzymes have biotechnological potential due to their ability to recognise cytosine DNA modifications that are present in up to 4% of the human genome. These epigenetic markers have roles in developmental processes, pluripotency of stem cells, neurodegenerative diseases and tumourigenesis. BrxU could therefore be used to map DNA modification sites and provide a platform to better understand the role of epigenetic markers in developmental and disease processes.
Aims: This project will use cross-disciplinary techniques to investigate BrxU-family enzymes. The student will (1) examine BrxU biochemistry, namely (i) sequence specificity, (ii) DNA-modification specificity and (iii) inhibition of BrxU by phage protein IPI; (2) perform BrxU structural studies to understand DNA-modification recognition and inhibition by IPI; (3) apply BrxU to map DNA modifications via NGS.
Supervisory Team: New England Biolabs are a global company with a proven track record in supplying tools and reagents for biotechnological and biomedical research. This expertise will be complemented by the structural biology capabilities at Durham University. Please visit https://www.blowerlab.com/.
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);
· a covering letter – clearly stating your first choice project, and optionally 2nd ranked project, 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;
· copies of your relevant undergraduate degree transcripts and certificates;
· a copy of your passport (photo page).
A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.
In addition to the above items, please email a completed copy of the Additional Details Form (as a 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]. The closing date for applications is 10th January 2022 at 5.00pm (UK time).
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