p53 modifications: exquisite decorations of the powerful guardian

Abstract

The last 40 years have witnessed how p53 rose from a viral binding protein to a central factor in both stress responses and tumor suppression. The exquisite regulation of p53 functions is of vital importance for cell fate decisions. Among the multiple layers of mechanisms controlling p53 function, posttranslational modifications (PTMs) represent an efficient and precise way. Major p53 PTMs include phosphorylation, ubiquitination, acetylation, and methylation. Meanwhile, other PTMs like sumoylation, neddylation, O-GlcNAcylation, adenosine diphosphate (ADP)-ribosylation, hydroxylation, and β-hydroxybutyrylation are also shown to play various roles in p53 regulation. By independent action or interaction, PTMs affect p53 stability, conformation, localization, and binding partners. Deregulation of the PTM-related pathway is among the major causes of p53-associated developmental disorders or diseases, especially in cancers. This review focuses on the roles of different p53 modification types and shows how these modifications are orchestrated to produce various outcomes by modulating p53 activities or targeted to treat different diseases caused by p53 dysregulation.

Keywords: acetylation; deacetylation; methylation; p53; phosphorylation; transcriptional regulation; ubiquitination.

Figure 1

Overview of p53 PTMs. The major sites for p53 modifications (phosphorylation, ubiquitination, sumoylation, neddylation, acetylation, methylation, O-GlcNAcylation, ADP-ribosylation, hydroxylation, and β-hydroxybutyrylation) are plotted. Different colors are used to differentiate distinct modification types. Representative functions of some modifications are indicated. The figure is mainly revised from Dai and Gu (2010) and Gu and Zhu (2012) and not drawn to scale.

Figure 2

PTMs can regulate p53 in different modes. (A) Phosphorylation at S33, T81, and S315 of p53 provides docking motif for Pin1. (B) Phosphorylations at p53 N-terminal mask it with negative electrostatic forces to facilitate the binding of CBP/p300 with positive electrostatic forces. (C and D) Mdm2 polyubiquitinates p53 for proteasomal degradation whereas monoubiquitinates it for nuclear export. (E) Acetylation at K120 by Tip60 may cause p53 conformational change, making it bind to specific target gene promoter. (F) Certain p53 modifications may help establish phase separation with other regulators.

Figure 3

Crosstalk between p53 modifications. There are widespread interplays between p53 modifications. These crosstalks can be divided into different types via diverse standards. For example, homogeneous modification crosstalk (phosphorylation of S15 boosts the latter phosphorylation at T18) vs. heterogeneous modification crosstalk (ubiquitination and acetylation compete for K320 and six C-terminal lysine residues), nearby modification crosstalk (methylation of K372 can promote acetylation of local K373 and K382) vs. distant modification crosstalk (phosphorylation at N-terminus influences the acetylation at C-terminus), or cooperative modification crosstalk (the case that K372 methylation promotes K373 and K382 acetylation can also be categorized as cooperative modification crosstalk) vs. antagonistic modification crosstalk (T377 and S378 phosphorylation inhibits K373 and K382 acetylation). For detailed discussion, see the context. Black arrows indicate positive effects. Red perpendicular bars indicate negative effects.

Figure 4

Targeting wild-type p53 modification for disease therapy. Various small-molecular compounds have been developed to target the major enzymes in wild-type p53 modification pathways. These targets and molecules include Mdm2 (Nutlins, TDP665759, and MI-319), Mdmx (SJ172550), Mdm2 and Mdmx (ATSP-7041), HAUSP (P22077, P5049, and HBX41108), and Sirt1 (tenovins). Black arrows indicate positive effects. Red perpendicular bars indicate negative effects.