The study investigates the role of post-translational modifications, particularly phosphorylation and acetylation, in the activation of p53 as a transcription factor following DNA damage. The authors show that p53 is acetylated at specific sites by histone acetyltransferases (HATs) p300 and PCAF, with p300 acetylating Lys-382 and PCAF acetylating Lys-320 in the carboxy-terminal region of p53. These acetylations enhance sequence-specific DNA binding. In vivo, p53 is acetylated at Lys-382 after exposure to UV light or ionizing radiation, and at Lys-320 after UV exposure. Phosphorylation at Ser-33 and Ser-37, which occur in response to DNA damage, inhibits acetylation by p300 and PCAF. The findings suggest that DNA damage enhances p53 activity through a phosphorylation-mediated cascade that leads to carboxy-terminal acetylation, which in turn facilitates sequence-specific DNA binding.The study investigates the role of post-translational modifications, particularly phosphorylation and acetylation, in the activation of p53 as a transcription factor following DNA damage. The authors show that p53 is acetylated at specific sites by histone acetyltransferases (HATs) p300 and PCAF, with p300 acetylating Lys-382 and PCAF acetylating Lys-320 in the carboxy-terminal region of p53. These acetylations enhance sequence-specific DNA binding. In vivo, p53 is acetylated at Lys-382 after exposure to UV light or ionizing radiation, and at Lys-320 after UV exposure. Phosphorylation at Ser-33 and Ser-37, which occur in response to DNA damage, inhibits acetylation by p300 and PCAF. The findings suggest that DNA damage enhances p53 activity through a phosphorylation-mediated cascade that leads to carboxy-terminal acetylation, which in turn facilitates sequence-specific DNA binding.