Our immune cells deliberately break their own DNA to generate the antibodies that fight viruses, bacteria, and cancer. This programme investigates why different DNA repair mechanisms are used at different stages of immune cell development, and how faults in these same repair processes cause bone marrow failure—a condition where the body can no longer produce enough blood cells. The problem is that we do not understand why inherited mutations in DNA repair genes sometimes cripple the immune system and sometimes cause bone marrow failure, or why both problems often occur together. The researchers predict that the same fundamental repair processes are at work in both contexts, but are used differently depending on the type of DNA damage involved. This is primarily fundamental science. By first defining how repair mechanisms operate in lymphocytes, the work will reveal how the body sustains blood production over a lifetime and prevents blood cancers. Understanding these core processes could eventually inform treatments for bone marrow failure syndromes and improve our knowledge of how the immune system maintains its adaptability as we age.
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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.
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