Chk2 is dispensable for p53-mediated G₁ arrest but is required for a latent p53-mediated apoptotic response

Abstract

In response to genotoxic stress, mammalian cells can activate cell cycle checkpoint pathways to arrest the cell for repair of DNA damage or induce apoptosis to eliminate damaged cells. The checkpoint kinase, Chk2, has been implicated in both of these responses and is believed to function in an ataxia telangiectasia (Atm)-dependent manner. We show here that Chk2−/− mouse embryo fibroblasts (MEFs), unlike Atm−/− or p53−/− MEFs, behaved like normal MEFs in manifesting p21 induction and G₁ arrest upon exposure to γ-irradiation. Therefore, Chk2 is not involved in p53-mediated G₁ arrest. To examine the role of Chk2 in p53-dependent apoptotic response, we used adenovirus E1A-expressing MEFs. We show that Chk2−/− cells, like p53−/− cells, did not undergo DNA damage-induced apoptosis, whereas Atm−/− cells behaved like normal cells in invoking an apoptotic response. Furthermore, this apoptosis could occur in the absence of protein synthesis, suggesting that it is preexisting, or “latent,” p53 that mediates this response. We conclude that Chk2 is not involved in Atm- and p53-dependent G₁ arrest, but is involved in the activation of latent p53, independently of Atm, in triggering DNA damage-induced apoptosis.

• DNA damage‖cell cycle control