Cellular stress conditions activate p53-dependent pathways to counteract the inflicted damage. To achieve the required functional diversity, p53 is subjected to numerous post-translational modifications and the expression of isoforms. Little is yet known how p53 has evolved to respond to different stress pathways. The p53 isoform p53/47 (p47 or ΔNp53) is linked to aging and neural degeneration and is expressed in human cells via an alternative cap-independent translation initiation from the 2nd in-frame AUG at codon 40 (+118) during endoplasmic reticulum (ER) stress. Despite an AUG codon in the same location, the mouse p53 mRNA does not express the corresponding isoform in either human or mouse-derived cells. High-throughput in-cell RNA structure probing shows that p47 expression is attributed to PERK kinase-dependent structural alterations in the human p53 mRNA, independently of eIF2α. These structural changes do not take place in murine p53 mRNA. Surprisingly, PERK response elements required for the p47 expression are located downstream of the 2nd AUG. The data show that the human p53 mRNA has evolved to respond to PERK-mediated regulation of mRNA structures in order to control p47 expression. The findings highlight how p53 mRNA co-evolved with the function of the encoded protein to specify p53-activities under different cellular conditions.

• MeSH
• eIF-2 Kinase genetics   metabolism   MeSH
• Humans MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Mice MeSH
• Tumor Suppressor Protein p53 * genetics   metabolism   MeSH
• Protein Processing, Post-Translational MeSH
• Protein Isoforms metabolism   MeSH
• Endoplasmic Reticulum Stress * genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• eIF-2 Kinase MeSH
• RNA, Messenger MeSH
• Tumor Suppressor Protein p53 * MeSH
• Protein Isoforms MeSH

DNA and RNA binding proteins (DRBPs) are a broad class of molecules that regulate numerous cellular processes across all living organisms, creating intricate dynamic multilevel networks to control nucleotide metabolism and gene expression. These interactions are highly regulated, and dysregulation contributes to the development of a variety of diseases, including cancer. An increasing number of proteins with DNA and/or RNA binding activities have been identified in recent years, and it is important to understand how their activities are related to the molecular mechanisms of cancer. In addition, many of these proteins have overlapping functions, and it is therefore essential to analyze not only the loss of function of individual factors, but also to group abnormalities into specific types of activities in regard to particular cancer types. In this review, we summarize the classes of DNA-binding, RNA-binding, and DRBPs, drawing particular attention to the similarities and differences between these protein classes. We also perform a cross-search analysis of relevant protein databases, together with our own pipeline, to identify DRBPs involved in cancer. We discuss the most common DRBPs and how they are related to specific cancers, reviewing their biochemical, molecular biological, and cellular properties to highlight their functions and potential as targets for treatment.

• Keywords
• DNA/RNA binding protein, biomarkers, cancer, mutation, targeted treatment,
• MeSH
• DNA-Binding Proteins metabolism   MeSH
• DNA MeSH
• Humans MeSH
• Neoplasms * genetics   metabolism   MeSH
• RNA-Binding Proteins * metabolism   MeSH
• RNA genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• DNA-Binding Proteins MeSH
• DNA MeSH
• RNA-Binding Proteins * MeSH
• RNA MeSH

Human cells are subjected to continuous challenges by different genotoxic stress attacks. DNA damage leads to erroneous mutations, which can alter the function of oncogenes or tumor suppressors, resulting in cancer development. To circumvent this, cells activate the DNA damage response (DDR), which mainly involves cell cycle regulation and DNA repair processes. The tumor suppressor p53 plays a pivotal role in the DDR by halting the cell cycle and facilitating the DNA repair processes. Various pathways and factors participating in the detection and repair of DNA have been described, including scores of RNA-binding proteins (RBPs) and RNAs. It has become increasingly clear that p53's role is multitasking, and p53 mRNA regulation plays a prominent part in the DDR. This review is aimed at covering the p53 RNA metabolism linked to the DDR and highlights the recent findings.

• Keywords
• ATM kinase, DNA damage response, MDM2, RNA metabolism, RNA-binding proteins, mRNA translation, p53,
• MeSH
• Humans MeSH
• RNA, Messenger metabolism   MeSH
• Mutation MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Untranslated Regions MeSH
• DNA Repair * physiology   MeSH
• DNA Damage * MeSH
• RNA-Binding Proteins genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• RNA, Messenger MeSH
• Tumor Suppressor Protein p53 MeSH
• Untranslated Regions MeSH
• RNA-Binding Proteins MeSH

The tumor suppressor protein p53 orchestrates cellular responses to a vast number of stresses, with DNA damage and oncogenic activation being some of the best described. The capacity of p53 to control cellular events such as cell cycle progression, DNA repair, and apoptosis, to mention some, has been mostly linked to its role as a transcription factor. However, how p53 integrates different signaling cascades to promote a particular pathway remains an open question. One way to broaden its capacity to respond to different stimuli is by the expression of isoforms that can modulate the activities of the full-length protein. One of these isoforms is p47 (p53/47, Δ40p53, p53ΔN40), an alternative translation initiation variant whose expression is specifically induced by the PERK kinase during the Unfolded Protein Response (UPR) following Endoplasmic Reticulum stress. Despite the increasing knowledge on the p53 pathway, its activity when the translation machinery is globally suppressed during the UPR remains poorly understood. Here, we focus on the expression of p47 and we propose that the alternative initiation of p53 mRNA translation offers a unique condition-dependent mechanism to differentiate p53 activity to control cell homeostasis during the UPR. We also discuss how the manipulation of these processes may influence cancer cell physiology in light of therapeutic approaches.

• Keywords
• ER stress, UPR, mRNA translation, p47, p53,
• Publication type
• Journal Article MeSH
• Review MeSH

Structured RNA regulatory motifs exist from the prebiotic stages of the RNA world to the more complex eukaryotic systems. In cases where a functional RNA structure is within the coding sequence a selective pressure drives a parallel co-evolution of the RNA structure and the encoded peptide domain. The p53-MDM2 axis, describing the interactions between the p53 tumor suppressor and the MDM2 E3 ubiquitin ligase, serves as particularly useful model revealing how secondary RNA structures have co-evolved along with corresponding interacting protein motifs, thus having an impact on protein - RNA and protein - protein interactions; and how such structures developed signal-dependent regulation in mammalian systems. The p53(BOX-I) RNA sequence binds the C-terminus of MDM2 and controls p53 synthesis while the encoded peptide domain binds MDM2 and controls p53 degradation. The BOX-I peptide domain is also located within p53 transcription activation domain. The folding of the p53 mRNA structure has evolved from temperature-regulated in pre-vertebrates to an ATM kinase signal-dependent pathway in mammalian cells. The protein - protein interaction evolved in vertebrates and became regulated by the same signaling pathway. At the same time the protein - RNA and protein - protein interactions evolved, the p53 trans-activation domain progressed to become integrated into a range of cellular pathways. We discuss how a single synonymous mutation in the BOX-1, the p53(L22 L), observed in a chronic lymphocyte leukaemia patient, prevents the activation of p53 following DNA damage. The concepts analysed and discussed in this review may serve as a conceptual mechanistic paradigm of the co-evolution and function of molecules having roles in cellular regulation, or the aetiology of genetic diseases and how synonymous mutations can affect the encoded protein.

• Keywords
• Ciona intestinalis, Intrinsically disordered proteins, Molecular basis of disease, Protein-RNA interactions, RNA world, Transcription factor, mRNA translation,
• MeSH
• Genetic Predisposition to Disease MeSH
• Protein Interaction Domains and Motifs MeSH
• Humans MeSH
• RNA, Messenger genetics   MeSH
• Tumor Suppressor Proteins genetics   metabolism   MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Neoplasms genetics   metabolism   pathology   MeSH
• RNA-Binding Proteins metabolism   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Gene Expression Profiling MeSH
• Transcriptome MeSH
• Protein Binding MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• RNA, Messenger MeSH
• Tumor Suppressor Proteins MeSH
• Tumor Suppressor Protein p53 MeSH
• RNA-Binding Proteins MeSH

p53 is an intrinsically disordered protein with a large number of post-translational modifications and interacting partners. The hierarchical order and subcellular location of these events are still poorly understood. The activation of p53 during the DNA damage response (DDR) requires a switch in the activity of the E3 ubiquitin ligase MDM2 from a negative to a positive regulator of p53. This is mediated by the ATM kinase that regulates the binding of MDM2 to the p53 mRNA facilitating an increase in p53 synthesis. Here we show that the binding of MDM2 to the p53 mRNA brings ATM to the p53 polysome where it phosphorylates the nascent p53 at serine 15 and prevents MDM2-mediated degradation of p53. A single synonymous mutation in p53 codon 22 (L22L) prevents the phosphorylation of the nascent p53 protein and the stabilization of p53 following genotoxic stress. The ATM trafficking from the nucleus to the p53 polysome is mediated by MDM2, which requires its interaction with the ribosomal proteins RPL5 and RPL11. These results show how the ATM kinase phosphorylates the p53 protein while it is being synthesized and offer a novel mechanism whereby a single synonymous mutation controls the stability and activity of the encoded protein.

• Keywords
• ATM kinase, MDM2, cell signaling, intrinsically disordered proteins, p53 messenger RNA, synonymous mutations,
• MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   metabolism   MeSH
• A549 Cells MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Phosphorylation genetics   physiology   MeSH
• Humans MeSH
• RNA, Small Interfering metabolism   MeSH
• RNA, Messenger metabolism   MeSH
• Mutation genetics   MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Polyribosomes metabolism   MeSH
• Proto-Oncogene Proteins c-mdm2 genetics   metabolism   MeSH
• Protein Stability MeSH
• Intrinsically Disordered Proteins genetics   metabolism   MeSH
• Blotting, Western MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ataxia Telangiectasia Mutated Proteins MeSH
• RNA, Small Interfering MeSH
• RNA, Messenger MeSH
• Tumor Suppressor Protein p53 MeSH
• Proto-Oncogene Proteins c-mdm2 MeSH
• TP53 protein, human MeSH Browser
• Intrinsically Disordered Proteins MeSH

Physiological and pathological conditions that affect the folding capacity of the endoplasmic reticulum (ER) provoke ER stress and trigger the unfolded protein response (UPR). The UPR aims to either restore the balance between newly synthesized and misfolded proteins or if the damage is severe, to trigger cell death. However, the molecular events underlying the switch between repair and cell death are not well understood. The ER-resident chaperone BiP governs the UPR by sensing misfolded proteins and thereby releasing and activating the three mediators of the UPR: PERK, IRE1 and ATF6. PERK promotes G2 cell cycle arrest and cellular repair by inducing the alternative translated p53 isoform p53ΔN40 (p53/47), which activates 14-3-3σ via suppression of p21CDKN1A. Here we show that prolonged ER stress promotes apoptosis via a p53-dependent inhibition of BiP expression. This leads to the release of the pro-apoptotic BH3-only BIK from BiP and activation of apoptosis. Suppression of bip mRNA translation is mediated via the specific binding of p53 to the first 346-nt of the bip mRNA and via a p53 trans-suppression domain located within the first seven N-terminal amino acids of p53ΔN40. This work shows how p53 targets BiP to promote apoptosis during severe ER stress and further illustrates how regulation of mRNA translation has a key role in p53-mediated regulation of gene expression during the UPR.

• MeSH
• Adaptor Proteins, Signal Transducing metabolism   MeSH
• Apoptosis physiology   MeSH
• Endoplasmic Reticulum Chaperone BiP MeSH
• Endoplasmic Reticulum metabolism   MeSH
• Endoribonucleases metabolism   MeSH
• Humans MeSH
• Mitochondrial Proteins metabolism   MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Protein Serine-Threonine Kinases metabolism   MeSH
• Apoptosis Regulatory Proteins metabolism   MeSH
• Heat-Shock Proteins metabolism   MeSH
• Unfolded Protein Response physiology   MeSH
• Endoplasmic Reticulum Stress physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adaptor Proteins, Signal Transducing MeSH
• Bik protein, mouse MeSH Browser
• Endoplasmic Reticulum Chaperone BiP MeSH
• Endoribonucleases MeSH
• Mitochondrial Proteins MeSH
• Tumor Suppressor Protein p53 MeSH
• Protein Serine-Threonine Kinases MeSH
• Apoptosis Regulatory Proteins MeSH
• Heat-Shock Proteins MeSH
• TP53 protein, human MeSH Browser