Cell type- and promoter-specific roles of Ser18 phosphorylation in regulating p53 responses

Phosphorylation of mouse p53 at Ser(18) occurs after DNA damage. To determine the physiological roles of this phosphorylation event in p53-dependent DNA damage responses, a Ser(18) to Ala missense mutation was introduced into the germline of mice. Thymocytes and fibroblasts from the knock-in mice show reduced transactivation of many p53 target genes following DNA damage. p53 protein stabilization and DNA binding are similar in knock-in and wild type mice, but C-terminal acetylation was defective, consistent with a role for Ser(18) in the recruitment of transcriptional co-activators. The apoptotic response of knock-in thymocytes to ionizing radiation is intermediate between that of wild type and p53 null thymocytes. Despite impaired transcriptional and apoptotic responses, the knock-in mice are not prone to spontaneous tumorigenesis. This indicates that neither phosphorylation of p53 on Ser(18) by ATM nor a full transcriptional response is essential to prevent spontaneous tumor formation in mice.