DNA damage responses in mammalian cells and their contribution to human health disorders; the end-stage.

我们身体里的所有细胞都携带着相同的基因信息，编码在DNA序列中。整个DNA序列代表了我们的基因组。我们的DNA不断受到外源性和内源性反应性化学物质的破坏。重要的是我们的基因组在没有任何序列变化的情况下保持稳定。维持基因组的稳定性对避免癌症和正常生长发育至关重要。基因组的稳定性是由DNA损伤反应机制维持的。在这种机制中受损的个体已经被描述过，并且可以表现出更高的癌症易感性、异常发育和/或对环境因子（如电离辐射（IR））的敏感性增强。我的实验室研究对DNA双链断裂（DSBs）的反应，当DNA分子的两条链在近距离断裂时，就会出现这种情况。dsb通常由暴露于IR引起。修复dsb的主要过程被称为DNA非同源末端连接（NHEJ）。MRC资助了我的实验室十多年来研究对dsb的反应。这项建议的目的是在我退休之前完成正在进行的工作方案。在工作的一个组成部分，我们已经证明了DNA的组织影响它的修复方式。很少使用的DNA区域比那些编码经常需要的蛋白质的DNA区域更紧密。最紧密的DNA，称为异染色质，比更开放的DNA修复得更慢，修复需要额外的蛋白质。我们将深入了解这一过程。免疫反应的发展需要产生识别不同抗原的多种细胞库。这是通过创建重新连接不准确的dsb来实现的。奇怪的是，细胞利用NHEJ在免疫发育过程中创造多样性，并在偶然形成DSB后保持稳定性。已经描述了NHEJ蛋白缺陷的患者，并表现出免疫缺陷和红外敏感性。他们在出生时也经常有小脑袋，这表明NHEJ是正常神经元发育所必需的。我们已经描述了一种名为LIG4综合征的疾病的小鼠模型。我们将完成对LIG4小鼠的分析，以深入了解LIG4患者小头表型的基础。最后，我们还研究了塞克尔综合征的基础，这是另一种导致小头和发育迟缓的疾病。我们已经确定了塞克尔综合征的遗传缺陷，并将完成目前对已确定蛋白质的研究。

All cells in our body carry the same genetic information encoded within the DNA sequence. The entire DNA sequence represents our genome. Our DNA is constantly damaged by exogenous and endogenously arising reactive chemicals. It is important that our genomes are stably maintained without any sequence changes. The maintenance of genomic stability is crucial for cancer avoidance and for normal growth and development. Genomic stability is maintained by DNA damage response mechanisms. Individuals impaired in such mechanisms have been described and can display elevated cancer predisposition, abnormal development and/or enhanced sensitivity to environmental agents such as ionizing radiation (IR). My laboratory studies the response to DNA double strand breaks (DSBs), which arise when both strands of the DNA molecule are broken in close proximity. DSBs are commonly induced by exposure to IR. The major process that repairs DSBs is called DNA non-homologous end-joining (NHEJ). The MRC has funded my laboratory for more than ten years to study the response to DSBs. The aim of this proposal is to complete the ongoing programme of work prior to my retirement. In one component of work, we have shown that the organization of DNA influences how it is repaired. DNA regions that are rarely used are more highly compacted than those that encode proteins that are required frequently. The most highly compacted DNA, called heterochromatin, is repaired more slowly than more open DNA and the repair requires additional proteins. We will seek insight into this process. The development of the immune response requires the creation of a diverse repertoire of cells that recognize different antigens. This is achieved by the creation of DSBs which are rejoined inaccurately. Curiously cells utilize NHEJ to create diversity during immune development and to maintain stability after accidental DSB formation. Patients defective in NHEJ proteins have been described and show immunodeficiency as well as IR sensitivity. They also frequently have small heads at birth demonstrating that NHEJ is required for normal neuronal development. We have characterised a mouse model for one such disorder called LIG4 Syndrome. We will complete the analysis of LIG4 mice to gain insight into the basis underlying the small head phenotype of LIG4 patients. Finally, we have also examined the basis underlying Seckel Syndrome, another disorder conferring small heads and developmental delay. We have identified genetic defects for Seckel Syndrome and will complete our current studies on the identified proteins.