Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• Lysine acetylation is a key post-translational modification regulating protein function.
• The role of C-terminal domain (CTD) acetylation of p53 (also known as TP53) in protein interactions and function remains incompletely understood.
• Bromodomain proteins are known 'readers' of acetylated lysine residues.

Purpose of the Study:

• To identify novel protein interactors of p53 whose binding is dependent on CTD acetylation status.
• To elucidate the mechanism by which the oncoprotein SET regulates p53 activity.
• To characterize the role of acetylation-dependent interactions in p53-mediated tumor suppression.

Main Methods:

• Proteomic screening to identify p53-interacting proteins.
• Biochemical assays to assess protein-protein interactions and transcriptional activity.
• In vivo studies using mouse xenograft and knock-in models.

Main Results:

• The oncoprotein SET was identified as a major p53-interacting protein whose binding is regulated by p53 CTD acetylation.
• SET inhibits p53 transcriptional activity in unstressed cells, but this repression is abolished upon stress-induced p53 CTD acetylation.
• Loss of SET-p53 interaction activates p53, leading to tumor regression in vivo.
• SET's acidic domain acts as a 'reader' for unacetylated p53 CTD, a mechanism distinct from bromodomain readers.

Conclusions:

• Acidic domain-containing proteins, like SET, function as a novel class of acetylation-dependent regulators.
• Acetylation of p53 CTD modulates its interaction with SET and other acidic domain-containing regulators (e.g., VPRBP, DAXX, PELP1).
• This acetylation-dependent regulatory mechanism plays a significant role in p53 function and tumor suppression.