DNA-damage checkpoints are primarily activated by ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases, predominantly through the activation of the mediator kinases CHK2 and CHK1, respectively. Previous data indicated that another mediator kinase, mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2), which is a downstream kinase of the p38 MAPK, also functions in checkpoint activation in response to cellular stress, such as heat shock and UV irradiation. Therefore, Yaffe and colleagues investigated whether p38 and MAPKAPK2 are part of the DNA-damage signalling network.
The authors showed that the treatment of cells with the anticancer agents cisplatin, camptothecin and doxorubicin increased the activating phosphorylation of p38 and MAPKAPK2. Furthermore, the p38-dependent phosphorylation of MAPKAPK2 occurred downstream of ATR in response to cisplatin and camptothecin, and downstream of ATR and ATM in response to doxorubicin. A major effector of DNA-damage checkpoint activation is p53. The authors showed that the p38–MAPKAPK2 arm of the DNA-damage response pathway was required for the survival of mouse embryonic fibroblasts (MEFs) after treatment with doxorubicin or cisplatin only when p53 was not present. Moreover, they showed that MAPKAPK2 is required for the activation of the G2/M and intra-S phase checkpoints in Trp53−/− MEFs after treatment with doxorubicin and cisplatin. In this context, MAPKAPK2 was required for checkpoint activation upstream of cell division cycle 25A and B (CDC25A and CDC25B), despite the ATR-dependent activation of CHK1 in a parallel pathway.
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