Sci. STKE, 4 February 2003
Checkpoint Signals ATM Regulation Revealed
The protein kinase ATM (mutated in the human disease ataxia telangiectasia, which is associated with a high risk of cancer) is well known to function in cell cycle checkpoint signaling pathways that arrest the cell cycle in response to DNA damage. Now studies by Bakkenist and Kastan have extended our understanding of how the activity of this critical kinase is regulated. They identified an autophosphorylation site in the kinase and generated antibodies that specifically recognized the phosphorylated enzyme. This site of autophosphorylation was found to interact with the kinase domain in vitro. Protein cross-linking in cells treated with formaldehyde revealed that ATM was present as an inactive dimer in the absence of DNA damage, with the active site blocked from interaction with potential targets. The kinase became active in cells exposed to ionizing radiation, and the dimer dissociated after autophosphorylation took place. Experiments monitoring activation of ATM with the antibody to the autophosphorylation site revealed that even slight amounts of DNA damage rapidly activated ATM (within 15 min) and activated a large proportion of the ATM in the cell. The authors reasoned that direct activation of ATM bound to double-strand breaks in DNA was unlikely to account for such extensive activation, so they looked for more general changes in the nucleus that might influence more of the ATM molecules. They suspected changes in chromatin structure as one such alteration, and indeed agents that alter chromatin structure (but do not cause breaks) caused rapid phosphorylation of ATM. Although the precise nature of the damage detection mechanism remains to be resolved, the outlines of the critical pathways protecting the integrity of the genome are coming more clearly into focus.
C. J. Bakkenist, M. B. Kastan, DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499-506 (2003). [Online Journal]
Citation: ATM Regulation Revealed. Sci. STKE 2003, tw51 (2003).
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