Phosphorylation of murine p53 at Ser-18 regulates the p53 responses to DNAdamage

Ser-15 of human p53 (corresponding to Ser-18 of mouse p53) is phosphorylate d by ataxia-telangiectasia mutated (ATM) family kinases in response to ioni zing radiation (IR) and UV light, To determine the effects of phosphorylati on of endogenous murine p53 at Ser-18 on biological responses to DNA damage , we introduced a missense mutation (Ser-18 to Ala) by homologous recombina tion into both alleles of the endogenous p53 gene in mouse embryonic stem ( ES) cells. Our analyses showed that phosphorylation of murine p53 at Ser-18 in response to IR or UV radiation was required for a full p53-mediated res ponse to these DNA damage-inducing agents. In contrast, phosphorylation of p53 at Ser-18 was not required for ATM-dependent cellular resistance after exposure to IR, Additionally, efficient acetylation of the C terminus of p5 3 in response to DNA damage did not require phosphorylation of murine p53 a t Ser-18.