Regulation of Tip60-dependent p53 acetylation in cell fate decision

The acetylation of p53 plays an essential role in regulating its transcriptional activity. Nevertheless, how p53 acetylation is modulated in cell fate decision is less understood. We developed a network model to reveal how Tip60-dependent p53 acetylation is regulated to modulate cellular outcome. We proposed that p53 is progressively activated and exhibits distinct dynamics depending on the severity of DNA damage. For mild damage, p53 is primarily activated to trigger cell cycle arrest by transactivating p21, with its concentration showing pulses. For severe damage, p53 is acetylated at Lysine 120 (K120) by Tip60 to trigger apoptosis by inducing PUMA, and its concentration increases to high levels. Several p53-centered feedback loops coordinate to regulate its acetylation status, ensuring a robust decision on cell fate.