ATM Phosphorylation of Mdm2 Ser394 Regulates the Amplitude and Duration of the DNA Damage Response in Mice

SummaryDNA damage induced by ionizing radiation activates the ATM kinase, which subsequently stabilizes and activates the p53 tumor suppressor protein. Although phosphorylation of p53 by ATM was found previously to modulate p53 levels and transcriptional activities in vivo, it does not appear to be a major regulator of p53 stability. We have utilized mice bearing altered Mdm2 alleles to demonstrate that ATM phosphorylation of Mdm2 serine 394 is required for robust p53 stabilization and activation after DNA damage. In addition, we demonstrate that dephosphorylation of Mdm2 Ser394 regulates attenuation of the p53-mediated response to DNA damage. Therefore, the phosphorylation status of Mdm2 Ser394 governs p53 protein levels and functions in cells undergoing DNA damage.

► ATM phosphorylation of Mdm2 is required for IR-induced p53 activation in vivo
► Stabilization of p53 by ionizing radiation is due to ATM phosphorylation of Mdm2-S394
► ATM phosphorylation of Mdm2-S394 does not alter Mdm2 stability
► Phosphorylation of Mdm2 regulates the duration of the p53 response to DNA damage