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变性、免疫缺陷、放射敏感性和非常高的癌症发展风险。在这种综合征中有缺陷的基因产物ATM在1995年被鉴定出来，从那时起，它在保护细胞免受遗传损伤方面的作用已经被详细研究。ATM蛋白是一个非常大的分子，迄今为止只有一个功能区域已被描述。分子的其他区域很可能在细胞中发挥重要作用。该项目旨在研究蛋白质中其他结构域的重要性，以及是什么导致ATM被激活。我们已经开发出一种方法，使我们能够在ATM基因的任何地方引入变化，然后在生物读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于ATM的任何区域。我们将把重点放在我们有一些初步证据的地区。最后，我们将进行一个机制的研究，看看ATM是如何激活的。这些数据将有助于未来设计分子，以干扰ATM的功能，使肿瘤更容易接受放射治疗。

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.