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

DNA对所有生命（某些病毒除外）都是必不可少的，就像遗传和细胞形成所必需的基因蓝图一样。DNA本身是可以修饰的，众所周知，这些修饰（通常是由含有单个碳原子的侧链构成）对细胞的发育、对压力的反应和生存有着关键的影响。我们最近发现，在细菌中，DNA的某些片段可以通过由至少五个碳原子组成的更复杂的修饰来改变。至关重要的是，这种复杂的修饰对细菌有很高的毒性，尽管我们并不完全了解其中的原因。这些复杂的修饰是由一种叫做酶的蛋白质在DNA上添加和移除的，我们已经确定了这种酶。我们还发现，这种修饰发生在细菌中，这些细菌是导致人类疾病的重要原因，如结核病（全世界仍有许多人死于结核病）、大肠杆菌食物中毒，以及一种导致医院里的人患上严重疾病的超级细菌。在这个项目中，我们将通过在原子水平上研究作用于DNA的酶来研究复杂的DNA修饰是如何发生的，并找出修饰是如何被控制和去除的。这将使我们有机会非常详细地了解这一过程，并利用细菌本身设计一系列实验。我们将研究这个和相关的DNA修饰如何影响细菌的行为，包括它们引起疾病的能力。在未来，这项工作应该为我们提供所有的信息，在未来，可以让我们干扰这些酶，制造出治疗耐药细菌迫切需要的新抗生素。

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.