Understanding the activity and role of DarTG, a toxin:antitoxin system responsible for a novel DNA modification

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DNA is essential for all life (except for certain viruses) as is the genetic blueprint which is necessary for heredity and how cells are made. DNA itself can be modified and it is known that these modifications (which usually are made of side chains containing a single atom of carbon) have critical effects on how cells develop, respond to stress, and survive. We have recently discovered that in bacteria certain stretches of DNA can be altered by a much more complex modification consisting of at least five carbon atoms. Critically, this complex modification is highly toxic to bacteria, although we do not exactly understand why. These complex modifications are added to and removed from DNA by proteins called enzymes which we have identified. We have also found that this modification happens in bacteria which are important causes of human disease such as tuberculosis (which still kills many people across the world), E. coli food poisoning, and a superbug which causes serious disease in people in hospitals. In this project, we will study how the complex DNA modification occurs by studying the enzymes acting on DNA at an atomic level, and find out how the modification is controlled and removed. This will give us the opportunity to understand the process in great detail, and to devise a series of experiments using the bacteria themselves. We will look at how this and a related DNA modification affect the behaviour of bacteria, including their ability to cause disease. In the future this work should provide us with all the information that, in the future, could allow us to interfere with these enzymes to make new antibiotics that are desperately needed to treat resistant bacteria.