Function and Regulation of ATM: Mechanistic Studies

人类遗传性疾病共济失调-毛细血管扩张症的特征是神经退化、免疫缺陷、放射敏感性和非常高的癌症发展风险。这种综合征中有缺陷的基因产物ATM是在1995年被发现的，从那时起，人们就详细研究了它在保护细胞免受遗传损伤中的作用。ATM蛋白是一个非常大的分子，到目前为止只描述了一个功能区。该分子的其他区域很可能对其在细胞中的功能也很重要。这个项目旨在调查蛋白质中其他结构域的重要性，以及是什么导致ATM被激活。我们已经开发了一种方法，允许我们在ATM基因的任何地方引入变化，然后在生物读取剪切试验中测试这些变化的影响。这种方法将使我们能够将功能重要性归因于ATM的任何区域。我们将把重点放在我们有一些初步证据表明活动的地区。最后，我们将进行一个机制研究，看看自动取款机是如何被激活的。这些数据将有助于未来设计分子来干扰ATM的功能，使其应用于使肿瘤更容易接受放射治疗的应用。

The human genetic disorder ataxia-telangiectasia is characterised by neurodegeneration, immunodeficiency, radiosensitivity and a very high risk for development of cancer. The gene product defective in this syndrome, ATM, was identified in 1995 and since then its role in protecting the cell against genetic damage has been investigated in some detail. The ATM protein is a very large molecule and to date only one functional region has been described. It is very likely that other regions of the molecule will be important in its function in the cell. This project is designed to investigate the importance of other domains in the protein and also what it is that causes ATM to be activated. We have developed a methodology which allows us to introduce changes anywhere in the ATM gene and then test the effects of these changes in a biological read-cut assay. This approach will enable us to ascribe functional significance to any region of ATM. We will focus on regions where we have some preliminary evidence for activity. Finally we will carry out a mechanistic study to see how ATM is activated. These data will be useful in future design of molecules to interfere with the function of ATM in applications designed to make tumours more receptive to radiotherapy.