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Understanding the molecular mechanism of the Maestri innate bacterial immune system and its synergy with CRISPR‐Cas

   School of Biochemistry

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  Prof M D Szczelkun, Prof Mark Dillingham, Dr E Westra  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Prokaryotes have evolved over billions of years alongside their viruses, the bacteriophages, or “phages”. To prevent viral infection, prokaryotes have evolved rudimentary immune mechanisms, the most widespread and well‐studied of which are the Restriction‐Modification and the CRISPR‐Cas enzymes. These prokaryotic “defence systems” are important regulators of horizonal gene transfer, for example affecting the acquisition of antibiotic resistance genes. They have also led to two revolutions in science: the advent of the age of cloning and the age of gene editing. These breakthroughs have been built on numerous biochemical and biophysical studies that have shed light on the molecular mechanisms of these systems. Excitingly, in recent years the discovery of prokaryotic defence systems has accelerated, and hundreds of diverse systems have been identified, the vast majority of which are completely mysterious. These systems often co‐exist in the same strain, with bacteria having on average 6 systems. We are now in a new age of discovery of prokaryotic defence biology where we need to understand how these new systems work and whether there are synergistic interactions between different systems.

In this collaborative project between the Szczelkun lab (Bristol) and the Westra lab (Exeter), and working together with a collaborative team from the Universities of Bath, Bristol, Durham, Exeter, Liverpool, Manchester and St. Andrews, funded as part of a BBSRC sLoLa grant, you will study a newly‐identified bacterial defence, called Maestri. This novel innate immune system appears to use epigenetic modifications to prevent auto‐immunity, like RM enzymes. But the combination of genes is unique and includes genes of unknown function. It has also been discovered that Maestri can work in synergy with CRISPR‐Cas systems when preventing phage infection. Your role will be to discover how Maestri works. You will use purified proteins to establish the subunit‐subunit interactions, and how they interact with nucleic acids (DNA and RNA) and nucleotides (ATP). You will then use enzyme assays to establish the properties of the system, leading to models for its anti‐phage activity that can be probed in cells. You will be based in the Szczelkun lab which is supported by funding from the BBSRC and ERC, and is part of the thriving and collegiate School of Biochemistry at the University of Bristol. There will be close collaboration with the Westra lab in Exeter. For students who might want to study part‐time, during periods of protein purification a full‐time effort will be required.

Our aim as the SWBio DTP is to support students from a range of backgrounds and circumstances.  Where needed, we will work with you to take into consideration reasonable project adaptations (for example to support caring responsibilities, disabilities, other significant personal circumstances) as well as flexible working and part‐time study requests, to enable greater access to a PhD.  All our supervisors support us with this aim, so please feel comfortable in discussing further with the listed PhD project supervisor to see what is feasible.

Information on “How to Apply” is available here:  https://www.swbio.ac.uk/programme/projects-available/. When applying to the University of Bristol, please use the following link: Start your application | Study at Bristol | University of Bristol. To choose the correct programme, please start to type 'South West' in the search box and the SWBio programme will appear. When making your application, please indicate the supervisor name and the project title on the form. Ensure you provide all supporting documents as per the programme admissions statement.

Funding Notes

Application deadline: Midnight, Monday 5 December 2022
This is a 4 year PhD studentship fully funded by the BBSRC, SWBio Doctoral Training Partnership. Full details on the BBSRC SWBio DTP programme can be found at: https://www.swbio.ac.uk/programme/projects-available/. This link includes information on projects available, eligibility requirements and the selection process.
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