Ubiquitylation within and beyond the DNA damage response

随着年龄的增长，我们的细胞对基因构成中的累积损伤变得越来越敏感，而基因构成是由一种叫做DNA的复杂分子构成的。DNA损伤经常发生，例如通过辐射、阳光、烟草烟雾中的化学物质，甚至来自我们呼吸的空气中的氧气。DNA损伤的增加与阻止我们健康衰老的一些最严重和最常见的问题有关。这包括癌症和大脑疾病，如智力丧失。事实上，某些永久性的DNA变化会影响细胞修复DNA损伤的能力，从而导致这些疾病的早期发作和过早衰老。随着全球人口老龄化，与年龄有关的疾病负担将稳步增加。因此，我们迫切需要更好地了解细胞如何防止DNA损伤。这可以找到预防这些疾病的方法，从而促进整个生命周期的健康老龄化。为了防止永久性的DNA损伤，细胞已经找到了许多不同的方法来修复受损的DNA。数以百计的蛋白质——细胞的主力——需要以高度有组织的方式快速改变它们的行为，这是一项令人惊叹的壮举，目前还远未被正确理解。虽然细胞可以利用一个精心设计的工具箱来实现这一点，但下面的方法尤其令人着迷：一种被称为泛素的小蛋白质附着在其他蛋白质上。泛素可以以不同的方式连接，作为一个单一的泛素或由许多泛素以不同的方式粘合在一起的多泛素链。泛素附着的过程称为泛素化。泛素化蛋白被其他蛋白质识别，从而触发泛素化蛋白行为的最终变化。泛素化依赖于几个酶群，包括已知的E2s。我最近发现几个E2s在修复DNA损伤中起着重要作用。通过使用我一直在开发的新技术，该提案的主要目的之一是更好地理解不同的E2s如何精确地完成DNA修复。这可以突出它们作为药物靶点的潜力，这意味着它们可以被药物改变以产生理想的效果。例如，这种效果可以用于治疗与年龄有关的疾病，如癌症。此外，我最近的发现表明，识别和翻译泛素化蛋白的蛋白质比目前预期的要多得多。因此，该提案的另一个关键目标是分析这些泛素结合蛋白。通过这样做，提出的工作将改变我们对不同泛素化如何以确定的有组织的方式改变蛋白质行为的理解。这些发现可能对商业部门具有吸引力，因为它们有可能发展成为通用的泛素研究工具。由于泛素化几乎涉及细胞生物学的各个方面，因此提出的工作可能会对这方面产生广泛的影响。总之，拟议的研究将增加我们对泛素化如何调节DNA损伤反应和相关过程的基本知识。这对维持DNA的完整性至关重要。鉴于DNA损伤反应对预防各种与年龄有关的疾病的重要性，这项工作可能为开发有助于整个生命健康衰老的新药铺平道路。

As we age our cells become increasingly sensitive to accumulating damage in their genetic makeup, which is formed by a complex molecule called DNA. DNA damage happens frequently, for instance through radiation, sunlight, chemicals in tobacco smoke, and even from the oxygen in the air we breathe. A rise in DNA damage is linked to some of the most severe and common problems that prevent us from healthy ageing. This includes cancer and diseases of the brain, such as loss of mental abilities. In fact, certain permanent DNA changes that affect the ability of cells to repair DNA damage, can lead to an early onset of these diseases and to premature ageing itself. With the global population ageing, the burden of age-related disorders will steadily increase. It is therefore of urgent importance that we understand better how cells prevent DNA damage. This could lead to ways to prevent these disorders and thus, contribute to healthy ageing across the lifespan.To prevent permanent DNA damage, cells have found many different ways to repair the damaged DNA. Hundreds of proteins -the workhorses of the cell- need to quickly change their behaviour in highly organised ways, an amazing feat that is far from being properly understood. While cells can make use of an elaborate toolkit for this, the following way is especially fascinating: a little protein, known as ubiquitin, is attached to other proteins. Ubiquitin can be attached in different ways, as a single ubiquitin or as poly-ubiquitin chains made up of many ubiquitins glued together in different ways. The process of ubiquitin attachment is called ubiquitylation. The ubiquitylated proteins are recognised by other proteins, which trigger the final change in the behaviour of the ubiquitylated protein. Ubiquitylation relies on several enzyme groups, including ones known as E2s. I have recently found that several E2s play fundamental roles in repairing DNA damage. Through using novel techniques that I have been key in developing, one of the major aims of the proposal is to better understand how precisely different E2s accomplish DNA repair. This could highlight their potential as drug targets, meaning that they could be changed by a medicine to give a desirable effect. Such an effect could for instance be towards treating age-related diseases such as cancer. Moreover, my recent findings suggest that many more proteins recognise and translate ubiquitylated proteins than is currently expected. Another key aim of the proposal is therefore to analyse these ubiquitin binding proteins. By doing so the proposed work will transform our understanding of how different ubiquitylations change the behaviour of proteins in defined organised ways. These discoveries could be attractive to the commercial sector, as they have potential to be developed into general ubiquitin research tools. Since ubiquitylation is involved in almost every aspect of cell biology, the proposed work is likely to have a wide impact regarding this.Taken together, the proposed research will increase our fundamental knowledge of how ubiquitylation regulates the DNA damage response and associated processes. This is crucial to maintaining DNA integrity. Given the significance of the DNA damage response for preventing various age-related disorders, the work may pave the way for the development of new medicines contributing to healthy ageing throughout life.