DNA DAMAGE-INDUCED PHOSPHORYLATION OF P53 ALLEVIATES INHIBITION BY MDM2

DNA-damaging agents signal to p53 through as yet unidentified posttran scriptional mechanisms. Here we show that phosphorylation of human p53 at serine 15 occurs after DNA damage and that this leads to reduced i nteraction of p53 with its negative regulator, the oncoprotein MDM2 in vivo and in vitro. Furthermore, using purified DNA-dependent protein kinase (DNA-PK), we demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of MDM2 to inhibit p53-dependent transa ctivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our st udies provide a plausible mechanism by which the induction of p53 can be modulated by DNA-PK (or other protein kinases with similar specific ity) in response to DNA damage.