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.

Cell Fate Regulation upon DNA Damage: p53 Serine 46 Kinases Pave the Cell Death Road

“…Although it is still not understood how p53 exactly shapes the different cell fate decisions, transcriptional activation of different target gene sets as well as non‐transcriptional effects in the cytoplasm on mitochondrial outer‐membrane permeabilization (MOMP) are involved. The plasticity of the p53 response is regulated by the temporal expression patterns of p53, its interaction with other proteins as well as post‐translational modifications of p53 (for more detailed information we recommend some recent reviews). Whereas the p53 phosphorylation marks at Ser15 and Ser20 occur both upon mild and massive DNA damage and are critical to stabilize p53 by breaking the interaction with the negative regulatory ubiquitin ligase MDM2, there is one particular phosphorylation mark on p53 reported, phosphorylation at Serine residue 46, which is selectively linked to its cell killing activity upon severe genotoxic stress (Figure ).…”

Fine tuning of p53 functions between normal and leukemic cells: a new strategy for the treatment of chronic lymphocytic leukemia

“…Under moderate levels of DNA damage, p53 facilitates growth arrest enabling DNA repair, whereas excessive DNA damage causes p53 to initiate programmed cell death -apoptosis. 13 This ability of p53 to induce apoptosis in cells under genotoxic stress serves as the underlying mechanism of killing by many chemotherapeutic drugs.…”

p53 induces ARTS to promote mitochondrial apoptosis

“…p53 is such detrimental to cancer cells that several auto-regulatory mechanisms have been evolved in cancer cells to control its activity (Zhou et al, 2017). The E3-ubiquitin ligase MDM2, encoded by a p53 target gene, is the master negative regulator that can inhibit p53 activity by directly concealing its transcriptional activation domain (TAD) and promoting its proteolytic degradation (Liu et al, 2019, Oliner et al, 1993, Haupt et al, 1997, Kubbutat et al, 1997.…”