p53 transcriptional activity is essential for p53-dependent apoptosis following DNA damage

p53-mediated transcription activity is essential for cell cycle arrest, but its importance for apoptosis remains controversial. To address this questi on, we employed homologous recombination and LoxP/Cre-mediated deletion to produce mutant murine embryonic stem (ES) cells that express p53 with Gin a nd Ser in place of Leu25 and Trp26, respectively. p53(Gln25Ser26) was stabl e but did not accumulate after DNA damage; the expression of p21/Waf1 and P ERP was not induced, and p53-dependent repression of MAP4 expression was ab olished. Therefore, p53(Gln25Ser26) is completely deficient in transcriptio nal activation and repression activities. After DNA damage by UV radiation, p53(Gln25Ser26) was phosphorylated at Ser18 but was not acetylated at C-te rminal sites, and its DNA binding activity did not increase, further suppor ting a role for p53 acetylation in the activation of sequence-specific DNA binding activity. Most importantly, p53(Gln25Ser26) mouse thymocytes and ES cells, like p53(-/-) cells, did not undergo DNA damage-induced apoptosis. We conclude that the transcriptional activities of p53 are required for p53 -dependent apoptosis.