Structural Mechanism of the Bromodomain of the Coactivator CBP in p53 Transcriptional Activation

Lysine acetylation of the tumor suppressor protein p53 in response to a wide variety of cellular stress signals is required for its activation as a transcription factor that regulates cell cycle arrest, senescence, or apo- ptosis. Here, we report that the conserved bromo-domain of the transcriptional coactivator CBP (CREB binding protein) binds specifically to p53 at the C-terminal acetylated lysine 382. This bromodomain/acetyllysin binding is responsible for p53 acetylation-dependent coactivator recruitment after DNA damage, a steessential for p53-induced transcriptional activation of the cyclin-dependent kinase inhibitor p21 in G1 cell cycle arrest.We further present the three-dimensional nuclearmagnetic resonance structure of the CBP bro-modomain in complexwith a lysine 382-acetylated p53 peptide. Using structural and biochemical analyses, we define themolecular determinants for the specificity of this molecular recognition.