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

DNA断裂的修复对细胞的存活和预防致癌突变至关重要。然而，我们免疫系统的白细胞（淋巴细胞）在其发育的特定阶段有意地在某些基因内产生DNA断裂，并以此为手段有意地产生突变，从而改变它们产生的抗体和抗原防御分子的类型。实现这一点对我们的免疫系统至关重要，因为这种突变和适应这些基因的能力使我们的细胞能够产生防御能力，抵消不同的威胁，如病毒、细菌甚至癌细胞。DNA修复对不同血细胞的发育也很重要，随着年龄的增长，它也支持血液的长期生产。我们知道这一点，因为遗传了基因缺陷的人会改变他们修复DNA断裂的能力，他们通常会失去产生血液的能力，这种疾病被称为骨髓衰竭。我们最近的研究发现了几个DNA修复机制，它们对我们免疫系统的功能很重要。该计划的一个目标是研究为什么不同类型的相关DNA修复机制对淋巴细胞发育的不同方面都很重要。我们预测这些差异可以通过它们进化修复的不同类型的DNA损伤来解释。一些编码参与这些过程的DNA修复机器的基因也在遗传性罕见的人类骨髓衰竭综合征中发生突变。我们预测这两种功能都与共同的过程有关。通过首先在淋巴细胞中定义这些，我们还将了解我们的身体如何支持血液的长期生产，并预防血癌。

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.