Cell cycle regulation of the NHEJ DNA double-strand break repair pathway in eukaryotes

我们的细胞含有DNA，即所谓的“生命的遗传蓝图”，它为我们的基因编码信息。DNA具有简单的重复结构，由两条互补的DNA链组成，形成双螺旋结构。DNA的完整性不断受到各种DNA损伤剂的挑战。这些物质包括来自太阳的高能紫外线和x射线辐射，化学物质（包括人造的和环境的），甚至我们呼吸的氧气都可以攻击和破坏DNA。近年来，人们已经意识到，我们自己的细胞会产生大量不同的蛋白质，负责修复这种DNA损伤，如果不加以控制，将导致我们基因组DNA的不稳定。现在人们认识到，基因组不稳定是主要人类疾病（如癌症）发展的主要驱动因素之一。这些蛋白质“机器”可以剪切和替换异常的DNA突变/结构，并将断裂的DNA链拼接在一起。其中一个机器是非同源末端连接（NHEJ） DNA断裂修复复合体。这种修复装置能够检测到DNA螺旋中的物理断裂，将末端重新组合在一起，如果需要的话重新塑造它们，最后重新密封这些断裂，以恢复双链DNA的连续性。然而，如果不加以控制，这些修复机器的过剩也可能会干扰正常的细胞过程，如DNA复制和细胞分裂，从而产生危险的后果。这项建议的重点是了解我们的细胞如何控制这些修复复合体，以确保它们在需要时可用，但重要的是，当它们可能对细胞有害时被关闭。

Our cells contain DNA, the so called "genetic blueprint of life" which encodes the information for our genes. DNA has a simple repeating structure composed of two complementary strands of DNA, which form a double-helix structure. The integrity of DNA is constantly being challenged by various DNA-damaging agents. These agents include high energy UV and X-ray radiation from the sun, chemicals (both man-made and environmental) and even the oxygen we breathe can attack and damage DNA. In recent years, it has been realised that our own cells produce a large number of different proteins responsible for repairing this DNA damage which, if left unchecked, would lead to the destabilization of our genomic DNA. It is now recognized that genome instability is one of the major drivers for the development of major human diseases, such as cancer. These protein "machines" can cut out and replace aberrant DNA mutations/structures and splice together broken DNA strands. One such machine is the non homologous end-joining (NHEJ) DNA break repair complex. This repair apparatus is able to detect physical breaks in the DNA helices, bring the ends back together, remodel them if required and, finally, reseal these breaks to restore the continuity of the double-strand DNA. However, if unregulated, an over abundance of these repair machines could potentially also have dangerous consequences by interfering with normal cell processes, such as DNA replication and cell division. The focus of this proposal is to understand how our cells control these repair complexes to ensure they are available when required but, importantly, switched off when they are likely to be harmful to the cell.