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¹ Department of Molecular Pathology, Cancer Research Institute, Kanazawa University, Kanazawa, 13-1 Takaramachi, Ishikawa 920-0934, Japan
² Department of Environmental Science, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Ibaraki 310-8512, Japan
³ Radiation Biology Center, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan
⁴ Graduate School of Bioagricultural Science, Nagoya University, Nagoya 464-8601, Japan

ATM (ataxia-telangiectasia mutated) is activated by a variety of noxious agent, including oxidative stress, and ATM deficiency results in an anomalous cellular response to oxidative stress. However, the mechanisms for ATM activation by oxidative stress remain to be established. Furthermore, it is not clear whether ATM responds to oxidative DNA damage or to a change in the intracellular redox state, independent of DNA damage. We found that ATM is activated by N-methyl-N'-nitro-nitrosoguanidine (MNNG) and 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂), in NBS1- or MSH6-deficient cells. We further found that ATM is activated by treating chromatin-free immunoprecipitated ATM with MNNG or 15d-PGJ₂, which modifies free sulfhydryl (SH) groups, and that 15d-PGJ₂ binds covalently to ATM. Interestingly, 15d-PGJ₂-induced ATM activation leads to p53 activation and apoptosis, but not to Chk2 or H2AX phosphorylation. These results indicate that ATM is activated through the direct modification of its SH groups, independent of DNA damage, and this activation leads, downstream, to apoptosis.

^* Correspondence: E-mail: kyamamot{at}kenroku.kanazawa-u.ac.jp