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The mechanisms of targeting and cleavage of modified DNA by the Type IV restriction enzymes

About This PhD Project

Project Description

Interactions between bacteria and their viruses (bacteriophages) over billions of years have led to the evolution of a wide range of bacterial mechanisms to resist viral infection. The exploitation of such systems has produced true revolutions in biotechnology; firstly, the restriction enzymes for genetic engineering, and secondly, CRISPR-Cas9 for gene editing. This project aims to unravel the mechanisms and consequences of another class of bacterial immune system, the Type IV restriction endonucleases. These enzymes cut covalently-modified bacteriophage DNA, for example, specifically targeting 5-methylcytosine and 5-hydroxymethylcytosine. Very little is known about Type IV restriction enzymes at a mechanistic level, or about their importance to the coevolution of prokaryotic-phage communities.

This interdisciplinary project will combine state-of-the-art biophysical and single molecule microscopy analysis in the Szczelkun lab to determine how Type IV enzymes search for modified sites on DNA, and how the subsequent DNA cleavage is activated. A better understanding of the mechanisms of Type IV enzymes will help in their development and exploitation as tools for the study of innate and pathological changes in human epigenomes. Additionally, to address the role of Type IV enzymes for bacteria, the project will also involve evolutionary ecology experiments in collaboration with the Edze Westra lab (University of Exeter). These will determine the fitness costs of encoding Type IV enzymes for individual cells and for cell populations. This will add to our understanding of how bacteria influence the acquisition of traits such as virulence or antibiotic resistance.

Keywords: epigenetics, bacterial immune systems, bacteriophage, enzymology, microscopy, amr

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