p53 regulation upon genotoxic stress: intricacies and complexities

Abstract

These authors contributed equally to this work.Keywords: cancer, genotoxic stress, miRNA, p53, post-translational modifications Abbreviations: miRNA, microRNA; ROS, reactive oxygen species; UTR, untranslated region p53, the revered savior of genomic integrity, receives signals from diverse stress sensors and strategizes to maintain cellular homeostasis. However, the predominance of p53 overshadows the fact that this herculean task is no one-man show; rather, there is a huge army of regulators that reign over p53 at various levels to avoid an unnecessary surge in its levels and sculpt it dynamically to favor one cellular outcome over another. This governance starts right at the time of p53 translation, which is gated by proteins that bind to p53 mRNA and keep a stringent check on p53 protein levels. The same effect is also achieved by ubiquitylases and deubiquitylases that fine-tune p53 turnover and miRNAs that modulate p53 levels, adding precision to this entire scheme. In addition, extensive covalent modifications and differential protein interactions allow p53 to trigger a tailor-made response for a given circumstance. To magnify the marvel, these various tiers of regulation operate simultaneously and in various combinations. In this review, we have tried to provide a glimpse into this bewildering labyrinth. We believe that further studies will result in a better understanding of p53 regulation and that new insights will help unravel many aspects of cancer biology.Regulation of any cellular pathway is essential to coordinate the heterogeneity and complexity of functions in multicellular organisms. Among the tumor suppressors, decoding the bewildering number of pathways that p53 is involved in has long been the holy grail of scientists. p53 is a master regulator that integrates signals from diverse nodes and thus it is of no surprise that it is the most commonly mutated gene in a huge array of cancers with varied origins. p53 has many weapons at its disposal to combat stress including cell cycle arrest, senescence, apoptosis, autophagy, and metabolic reprogramming. Paradoxically, some of the outcomes of p53 activation are disparate and contradictory, such as cell cycle arrest, which is prosurvival, versus apoptosis and senescence, which are directed toward eliminating irreversibly damaged cells. This indicates that p53 needs to be educated to sense the extent and type of damage and make an appropriate choice of the kind of response it is going to elicit. Extensive research on the regulation of p53 under diverse kinds of stresses including genotoxic stress, starvation, hypoxia, and oncogene activation clearly indicate that p53 protein is regulated at diverse levels, including synthesis, degradation, covalent modifications, subcellular localization, and differential interaction with other proteins. Moreover, all possible permutations and combinations of these are employed to modulate p53 specificity, tissue heterogeneity, and diversity of function. In light of this, we restrict this review to exclusi<!-->vely dis...

Putting p53 in Context

“…On one hand, p53 can induce qualitatively different programs that produce different biological outcomes depending on cell type and stimulus. One proposed mechanism for qualitatively modulating biological p53’s effects involves stimulus-dependent post-translational modifications (PTMs) that can alter p53 affinity for different target genes; for example, phospho-p53 (S46) or acetyl-p53 (K120) stimulates apoptosis, whereas PRMT5-methylated p53 activates p21 more readily than apoptotic genes (reviewed in Kumari et al, 2014). A broad array of other PTMs at many different sites in the p53 protein have been described to not only modify protein stability, but also influence target gene bias, such as SUMOylation, glycosylation, and prolyl isomerization (Kumari et al, 2014).…”

“…One proposed mechanism for qualitatively modulating biological p53’s effects involves stimulus-dependent post-translational modifications (PTMs) that can alter p53 affinity for different target genes; for example, phospho-p53 (S46) or acetyl-p53 (K120) stimulates apoptosis, whereas PRMT5-methylated p53 activates p21 more readily than apoptotic genes (reviewed in Kumari et al, 2014). A broad array of other PTMs at many different sites in the p53 protein have been described to not only modify protein stability, but also influence target gene bias, such as SUMOylation, glycosylation, and prolyl isomerization (Kumari et al, 2014). Moreover, one post-translational modification may enhance acquisition of another, unlocking additional layers of regulation of protein stability, protein-protein interaction, and biasing DNA-binding toward select target genes.…”

Ceramide Signaling and p53 Pathways

“…Still, in many cases, mechanisms for such differences are not known. It has been suggested that context-dependent posttranslational modifications of p53 may dictate the interaction with a specific gene target (Kumari, Kohli, & Das, 2014). In addition, the kinetics of the p53 activation and the architecture of core promoters play a role in defining cellular response in a specific case: short p53 activation with rapid assembly of preinitiation complex and few rounds of RNA polymerase II reinitiation taking place at the p21 core promoter, and sustained activation with slow assembly of preinitiation complex that supports multiple rounds of transcription in case of Fas/APO1 and PUMA (Gomes & Espinosa, 2010; Morachis, Murawsky, & Emerson, 2010).…”

The Evolution of Human Cancer Gene Duplications across Mammals

“…The genetic controls of cancer suppression in nature's giants has been the focus of much research (Abegglen et al 2015;Caulin et al 2015;Sulak et al 2016;Vazquez et al 2018;Tollis et al 2019), as well as in mammals with pronounced longevity such as naked mole rats (Heterocephalus glaber) (Seluanov et al 2009;Tian et al 2013). Low cancer mortality rates in elephants may be related to the redundancy provided by as many as 20 genomic copies of the tumor suppressor gene TP53 (Abegglen et al 2015;Caulin et al 2015;Sulak et al 2016), which is responsible for apoptosis, senescence, and cell-cycle arrest in the presence of damaged DNA (Kumari et al 2014). Elephant cells have a higher apoptotic response to DNA damage compared to humans (Abegglen et al 2015;Sulak et al 2016), suggesting programmed cell death rather than the repair of damaged DNA is the mechanism of cancer suppression in elephants.…”