For instance, the DNA damage-activated protein kinase (DNA-PK) phosphorylates p53 at Ser15 and Ser37, the former resulting in the dissociation of the p53-MDM2 complex. Several kinases can phosphorylate p53 at different sites and with some level of redundancy. Phosphorylation can lead to stabilization and nuclear accumulation of p53. The exquisite regulation of p53 comes in many flavors, such as post-translational modifications, which influence p53 stability or specificity of its target genes. Upon severe DNA damage, p53 regulates expression of genes whose products are involved in cell death mechanisms, such as down-regulation of BCL-2 and up-regulation of NOXA and PUMA. Early reports highlighted p53 as an important regulator of cell cycle progression through controlling expression of the CDK inhibitor p21, particularly in response to genotoxic insults. The transcriptional function of p53 is initiated by its direct binding to DNA. Such oscillations may help cells to recover from DNA damage and avoid excessive cell death or senescence due to chronic p53 activation. The p53-MDM2 regulatory loop generates oscillations at the level of both proteins, in response to the intensity and duration of diverse stressors. In this regulatory feedback loop, p53 regulates MDM2 at the transcription level and MDM2 regulates the activity of p53. As part of this intricate interplay, MDM2 can bind p53, potentially inhibiting MDM2 transactivation. MDM2 contains a p53 DNA-binding site, therefore, its expression can be regulated by p53’s abundance and transcriptional activity. Under physiological conditions, the level of p53 is maintained low mainly by the E3 ubiquitin ligase MDM2 that targets p53 for degradation. Biologically, p53 is at the heart of responses to numerous cellular stress insults, with DNA damage being the first stressor shown to stabilize p53. Today, it is well established that mutations in TP53 are shared by most types of human tumors. Next to insulin, p53 is the most studied protein in science history, at least in part due to p53’s many talents and the fact that it is commonly altered in cancer. These events, without doubt, paved the way for a better understanding of some fundamental aspects of cell biology and pathology. A year later, p53 was selected for the molecule of the year award. The year 2022 marks the 30th anniversary of one of the milestones in cell biology, discoveries that inspired the concept of p53 as the guardian of the genome. The diverse defects of RiBi and IRBC that predispose and/or contribute to severe human pathologies including developmental syndromes and cancer are then outlined, along with examples of promising small-molecule-based strategies to therapeutically target the RS- and particularly RiBi- stress-tolerance mechanisms to which cancer cells are addicted due to their aberrant DNA replication, repair, and proteo-synthesis demands. Next, the tantalizing, yet still rather foggy functional crosstalk between replication and RiBi (nucleolar) stresses is considered, followed by the more defined involvement of p53-mediated monitoring of the multistep process of RiBi, including the latest updates on the RPL5/RPL11/5 S rRNA-MDM2-p53-mediated Impaired Ribosome Biogenesis Checkpoint (IRBC) pathway and its involvement in tumorigenesis. We then highlight the emerging involvement of p53 as a key component of the DNA replication Fork Speed Regulatory Network and the mechanistic links of p53 with cellular checkpoint responses to replication stress (RS), the driving force of cancer-associated genomic instability. Here, we first provide concise introductory notes on the canonical roles of p53, the key interacting proteins, downstream targets and post-translational modifications involved in p53 regulation.

Among the most fruitful lines of p53 research in recent years have been the discoveries revealing the multifaceted roles of p53-centered pathways in the fundamental processes of DNA replication and ribosome biogenesis (RiBi), along with cellular responses to replication and RiBi stresses, two intertwined areas of cell (patho)physiology that we discuss in this review. Firmly established as the hub of cellular stress responses and tumor suppressor targeted in most malignancies, p53’s many talents continue to surprise us, providing not only fresh insights into cell and organismal biology, but also new avenues to cancer treatment. Despite several decades of intense research focused on understanding function(s) and disease-associated malfunction of p53, there is no sign of any “mid-life crisis” in this rapidly advancing area of biomedicine.

Free arf player