alexa ATM activation and DNA damage response.


Journal of Cancer Science & Therapy

Author(s): Lavin MF, Kozlov S

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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 in our understanding of the activation process. However, it is now evident that more than one autophosphorylation event is required and not surprisingly this process is also attenuated by phosphatases and other modifications such as acetylation are also implicated. This is further complicated by a recent report that autophosphorylation at S1987 (the mouse site corresponding to S1981) is dispensable for Atm activation in an Atm mutant mouse model. Use of cell extracts and in vitro approaches in the reconstruction of activation complexes have shed further light on what it takes to activate ATM. The aim here is to examine the evidence for the involvement of these various steps in ATM activation and attempt to put together a comprehensive picture of the overall process and its significance to DNA damage signaling. This article was published in Cell Cycle and referenced in Journal of Cancer Science & Therapy

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