DNA double-strand break repair in blood development and lymphocyte diversification

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The repair of breaks in our DNA is vital for the survival of cells and prevention of cancer causingmutations. However, the white blood cells of our immune systems (lymphocytes) intentionally generate DNA breaks within certain genes at very specific points in their development, and use these as a means to generate intentional mutations that alter the types of antibodies and antigen defence molecules they produce. Achieving this is vital for our immune systems, as this ability to mutate and adapt these genes enables our cells to create defences that neutralise different threats, such as viruses, bacteria and even cancer cells. DNA repair is also important for the development of different blood cells, and it also supports the long-term production of blood as we age. We know this because people who inherit genetic faults that alter their ability to repair DNA breaks often lose their ability to generate blood, a disease referred to a bone marrow failure. Our recent research has uncovered several of the DNA repair mechanisms that are important for function of our immune systems. One goal of this programme is to investigate why distinct types of a related DNA repair mechanism are important for different aspects of lymphocyte development. We predict these differences can be explained by the different types of DNA damage they have evolved to repair. Some of the genes that encode the DNA repair machines involved in these processes are also mutated in inherited rare human bone marrow failure syndromes. We predict that both functions are linked to common processes. By defining these first in lymphocytes, we will also learn about how our bodies support the long-term production of blood, and also prevent blood cancers.