Acetylation is indispensable for p53 activation

Area of Science:

• Molecular biology
• Cellular stress response
• Tumor suppression

Background:

• The tumor suppressor p53 is crucial for cellular responses to genotoxic stress.
• p53 activation requires disruption of its interaction with the inhibitor Mdm2.
• The precise role of p53 posttranslational modifications, like phosphorylation and acetylation, in its activation remains debated.

Purpose of the Study:

• To identify all major acetylation sites of p53.
• To determine if p53 acetylation is essential for its activation and function.
• To elucidate the mechanism by which p53 acetylation influences the p53-Mdm2 interaction.

Main Methods:

• Identification of p53 acetylation sites.
• Analysis of p53-dependent growth arrest and apoptosis in the presence or absence of acetylation.
• Investigation of Mdm2 recruitment to p53-responsive promoters.

Main Results:

• Loss of p53 acetylation completely abolished p53-dependent growth arrest and apoptosis.
• Acetylation of p53 abrogates Mdm2-mediated repression by preventing Mdm2 recruitment to target promoters.
• p53 activation via acetylation occurs independently of its phosphorylation status.

Conclusions:

• p53 acetylation is an indispensable event for the p53-mediated stress response.
• Acetylation destabilizes the p53-Mdm2 interaction, leading to p53 activation.
• This study clarifies the critical role of p53 acetylation in cellular stress response pathways.