Defining the molecular link between DNA repair and chromatin remodelling

这项研究探讨了植物如何检测，信号和修复DNA损伤。DNA对生长和繁殖至关重要，但不断受到细胞中存在的高活性化学物质和环境因素（包括致癌物，UVB和土壤污染物，如重金属）的破坏。单个DNA双链断裂足以导致细胞死亡，因此如果生物体要存活，DNA需要不断修复。修复的第一步是检测DNA损伤并发出信号。重要的是，细胞迅速识别并发出DNA损伤的信号，以最大限度地减少对生物体生长和发育的有害影响。在这项研究中，将在生物科学学院，利兹大学，我们将建立如何检测和修复DNA双链断裂使用的模式植物拟南芥。我们将建立在我们现有的DNA损伤和修复的知识在植物中，包括令人兴奋的最近的结果表明，DNA损伤的主要检测器，称为MRN复合物，与负责组蛋白（包装DNA和调节其可及性的蛋白质）的修饰的蛋白质相互作用。这一新的结果表明，细胞可以通过在DNA损伤检测和修复的早期阶段修饰断裂部位的组蛋白来发出DNA损伤的信号。在这个建议中，我们将测试这一假设，即组蛋白修饰在DNA修复中起着至关重要的早期作用。我们已经分离出缺乏我们新发现的组蛋白修饰蛋白的突变植物，在这项研究中，我们将看看DNA断裂是否在组蛋白修饰、修复速度和DNA“解包”方面有不同的处理方式。我们还将确定这些突变对植物承受DNA损伤能力的影响。重要的是，我们要了解这些信号传导过程中的植物，因为DNA损伤信号传导和修复是必要的，以允许作物在环境胁迫条件下生长，这些途径的失败将导致产量下降和有害突变在后代中的积累。鉴于气候变化，现在重要的是我们要了解植物如何应对环境压力，这将影响作物的生存和产量。由于许多过程在不同的生物体中是保守的，这些研究也可能对癌症，衰老和基因治疗具有重要意义。

This study investigates how plants detect, signal and repair DNA damage. DNA is essential for growth and reproduction but is constantly being damaged by highly reactive chemicals present in the cell and environmental factors including carcinogens, UVB and soil pollutants such as heavy metals. A single DNA double strand break is sufficient to cause cell death and DNA therefore needs to be continuously repaired if the organism is to survive. The first steps in repair are detection and signalling of DNA damage. It is important that the cell rapidly recognises and signals the presence of DNA damage to minimise the harmful effects on growth and development of the organism. In this study, to be undertaken at the Faculty of Biological Sciences, University of Leeds, we will establish how DNA double strand breaks are detected and repaired using the model plant Arabidopsis thaliana. We will build on our existing knowledge of DNA damage and repair in plants, including exciting recent results that show that the primary detector of DNA damage, termed the MRN complex, interacts with proteins responsible for the modification of histones (proteins that package DNA and regulate its accessibility). This novel result suggests a mechanism by which the cell can signal DNA damage by modifying histones at the site of the break in the very early stages of DNA damage detection and repair. In this proposal, we will test this hypothesis that histone modification plays a crucial early role in DNA repair. We have isolated mutant plants lacking our newly identified histone modifying proteins, and in this study we will see if DNA breaks are processed differently, in terms of histone modification, the rate of repair and the 'unpacking' of DNA. We will also determine the effects of these mutations on the ability of plants to withstand DNA damage. It is important that we understand these signalling processes in plants, as DNA damage signalling and repair is required to allow growth of crop plants in conditions of environmental stress, and failure of these pathways will result in reduced yields and the accumulation of deleterious mutations in future generations. In view of climate change, it is now important that we understand how plants respond to environmental stresses, which will impact on crop survival and yield. As many of the processes are conserved amongst different organisms, these studies may also have important implications for cancer, aging and gene therapy.