The study demonstrates that DNA damage leads to specific post-translational modifications of the p53 protein, specifically phosphorylation of the first 24 amino acids of p53, including three serine residues. Serine-15 is identified as one of the two serines that become phosphorylated following DNA damage induced by ionizing radiation (IR) or ultraviolet (UV) irradiation in multiple cell types. Phosphorylation of p53 on serine-15 does not affect the kinetics of p53 binding to or dissociating from DNA but correlates with enhanced transcription of downstream p53 target genes. The phosphorylation of p53 on serine-15 is detectable within 6 hours after IR in AT cells and within 1 hour in lymphoblasts from normal individuals. However, phosphorylation of p53 on serine-15 is similar in normal and AT cells after UV irradiation. The findings suggest that p53 is phosphorylated in response to DNA damage, and this de novo phosphorylation may be involved in the subsequent induction and activation of p53. While ATM affects the kinetics of p53 phosphorylation after IR, it is not absolutely required for phosphorylation of p53 on serine-15.The study demonstrates that DNA damage leads to specific post-translational modifications of the p53 protein, specifically phosphorylation of the first 24 amino acids of p53, including three serine residues. Serine-15 is identified as one of the two serines that become phosphorylated following DNA damage induced by ionizing radiation (IR) or ultraviolet (UV) irradiation in multiple cell types. Phosphorylation of p53 on serine-15 does not affect the kinetics of p53 binding to or dissociating from DNA but correlates with enhanced transcription of downstream p53 target genes. The phosphorylation of p53 on serine-15 is detectable within 6 hours after IR in AT cells and within 1 hour in lymphoblasts from normal individuals. However, phosphorylation of p53 on serine-15 is similar in normal and AT cells after UV irradiation. The findings suggest that p53 is phosphorylated in response to DNA damage, and this de novo phosphorylation may be involved in the subsequent induction and activation of p53. While ATM affects the kinetics of p53 phosphorylation after IR, it is not absolutely required for phosphorylation of p53 on serine-15.