ATM Activation and DNA Damage Response

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Abstract
Well before the gene (ATM) mutated in the human genetic disorder ataxia-telangiectasia (A-T) was described it was evident from the clinical, molecular and cellular phenotype of A-T that this gene would play a central role in the DNA damage response. Mutation of ATM causes defective cell cycle checkpoint activation,a reduced capacity for repair of DNA double strand breaks and abnormal apoptosis, all of which contribute to the major features of A-T including genome instability, increased cancer risk and neurodegeneration. While the exact mechanism of activation remains unknown, it is clear that the Mre11 complex plays an important role both in the recruitment of ATM to the sites of DNA damage and in the efficient activation of ATM. Although ATM responds to agents that produce double strand breaks in DNA, other stimuli are also capable of ATM activation. The description of autophosphorylation on S1981 of ATM and the ensuing transition from an inactive dimer to an active monomer represents a major milestone i...

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