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

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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.