Ataxia Telangiectasia-Mutated (ATM) kinase is a large protein that plays a critical role in detecting and repairing double strand DNA breaks in the cell. The inventors have discovered that ATM kinase activation is exquisitely sensitive to DNA damage and occurs by phosphorylation of a specific serine residue at position 1981 on the ATM kinase protein. Activation of ATM kinase can now be directly detected using antibodies that specifically recognize only the activated, serine phosphorylated form of this enzyme. This provides a way to detect exposure to radiation, oxidative stress, and other DNA damaging agents or to gauge an individual’s susceptibility to such agents. Screening methods for agents which can modulate ATM kinase activity are now possible based on this discovery. Inhibitors of ATM kinase are useful for enhancing the effects of radiation therapy. ATM kinase activators are contemplated to be useful to protect against cancers that arise from DNA damage.
Polyclonal and monoclonal antibodies that specifically recognize activated ATM kinase phosphorylated at serine 1981. Cell lines useful in screening methods.
ATM, DNA damage, radiosensitizer, cancer prevention
Granted Patents or Published Applications
US Patent Nos. 6,916,624; 7,108,992; 7,160,692; 7,279,290; additional U.S. applications pending
Related Scientific References
Bakkenist, C. et al, "DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation", Nature 421:499-506 (2003); see also related commentary by Bartek, J. and Lukas, J., Nature 421:486-488 (2003); Kastan, M.B. and Bartek, J, "Cell-cycle checkpoints and cancer", Nature 432:316-323 (2004).
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