Mechanism of activation of ATM by DNA double strand breaks and other stimuli

DNA双链断裂和其他刺激激活ATM的机制

• 批准号: nhmrc : 389877
• 负责人: Prof Martin Lavin
• 金额: $ 34.52万
• 依托单位: The University of Queensland
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2006
• 资助国家: 澳大利亚
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/mechanism-activation-atm-breaks-stimuli/82525
• 关键词: Mechanism; activation; ATM; DNA; double

The human genetic disorder ataxia-telangiectasia is a rare human disease characterised by cancer predisposition and neuronal degeneration. The gene defective in this disorder, ATM, plays a central role in recognising damage to the genetic material and activates a number of different cellular pathways designed to maintain stability of genome and minimise the risk of cancer and other pathologies. In this project we are investigating how the protein is activated from a dormant state to phosphorylate a series of substrates involved in cellular signaling. Information in this process is very significant since the genetic lesion that activates ATM is a double strand break in DNA which not only is a potentially lethal lesion to the cell but has also the capacity to destabilize the genetic material. Information on this mechanism will also be useful for the design of small molecules that might interfere with ATM activation and in this way make tumour cells more susceptible to radiotherapy.

人类遗传性疾病共济失调毛细血管扩张症是一种罕见的人类疾病，其特征是癌症易感性和神经元变性。在这种疾病中，有缺陷的基因ATM在识别遗传物质的损伤方面起着核心作用，并激活了许多不同的细胞通路，旨在维持基因组的稳定性，并将癌症和其他疾病的风险降至最低。在这个项目中，我们正在研究该蛋白如何从休眠状态被激活，从而磷酸化一系列参与细胞信号传导的底物。这个过程中的信息是非常重要的，因为激活ATM的遗传损伤是DNA中的双链断裂，这不仅是对细胞的潜在致命损伤，而且具有破坏遗传物质稳定的能力。关于这一机制的信息也将有助于设计可能干扰ATM激活的小分子，从而使肿瘤细胞更容易受到放射治疗的影响。