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DNA Damage Induced by Temozolomide Signals to both ATM and ATR: Role of the Mismatch Repair System

Istituto Dermopatico dell'Immacolata–Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (S.C., S.F., E.B., S.D.); Institute of Neurobiology and Molecular Medicine, National Research Council, Rome, Italy (G.S.); Section of Chemical Carcinogenesis, Istituto Superiore di Sanità, Rome, Italy (M.T.R.); and Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland (J.J.)

The mammalian mismatch repair (MMR) system has been implicated in activation of the G₂ checkpoint induced by methylating agents. In an attempt to identify the signaling events accompanying this phenomenon, we studied the response of MMR-proficient and -deficient cells to treatment with the methylating agent temozolomide (TMZ). At low TMZ concentrations, MMR-proficient cells were growth-inhibited, arrested in G₂/M, and proceeded to apoptosis after the second post-treatment cell cycle. These events were accompanied by activation of the ATM and ATR kinases, and phosphorylation of Chk1, Chk2, and p53. ATM was activated later than ATR and was dispensable for phosphorylation of Chk1, Chk2, and p53 on Ser15 and for triggering of the G₂/M arrest. However, it conferred protection against cell growth inhibition induced by TMZ. ATR was activated earlier than ATM and was required for an efficient phosphorylation of Chk1 and p53 on Ser15. Moreover, abrogation of ATR function attenuated the TMZ-induced G₂/M arrest and increased drug-induced cytotoxicity. Treatment of MMR-deficient cells with low TMZ concentrations failed to activate ATM and ATR and to cause phosphorylation of Chk1, Chk2, and p53, as well as G₂/M arrest and apoptosis. However, all these events occurred in MMR-deficient cells exposed to high TMZ concentrations, albeit with faster kinetics. These results demonstrate that TMZ treatment activates ATM- and ATR-dependent signaling pathways and that this process is absolutely dependent on functional MMR only at low drug concentrations.

Address correspondence to: Stefania D'Atri, Istituto Dermopatico Dell'Immacolata (IDI-IRCCS), Via Monti di Creta 104, 00167 Rome, Italy. E-mail: s.datri{at}idi.it

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