ArticleJournal of molecular cell biology2019
A single synonymous mutation determines the phosphorylation and stability of the nascent protein.
Article in Journal of molecular cell biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 55 citations in OpenAlex.
- The p21 resilience network: a conceptual framework linking senescence to ferroptosis and cuproptosis resistance.NPJ systems biology and applications · 2026Review
- TheiScience · 2025Article
- A cancer-associated TP53 synonymous mutation induces synthesis of the p53 isoform p53/47.British journal of cancer · 2025Article
- Structure and function of MDM2 and MDM4 in health and disease.The Biochemical journal · 2025Review
- The DNA damage sensor ATM kinase interacts with the p53 mRNA and guides the DNA damage response pathway.Molecular cancer · 2024Article
- Pinostrobin, a fingerroot compound, regulates miR-181b-5p and induces acute leukemic cell apoptosis.Scientific reports · 2023Article
- The p53 endoplasmic reticulum stress-response pathway evolved in humans but not in mice via PERK-regulated p53 mRNA structures.Cell death and differentiation · 2023Article
- Article
- When a Synonymous Variant Is Nonsynonymous.Genes · 2022Article
- Synonymous Variants: Necessary Nuance in Our Understanding of Cancer Drivers and Treatment Outcomes.Journal of the National Cancer Institute · 2022Review
- The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer.Molecular biology and evolution · 2022Article
- Codon-specific Ramachandran plots show amino acid backbone conformation depends on identity of the translated codon.Nature communications · 2022Article
- Review
- Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?Cellular & molecular biology letters · 2021Review
- Review
- Synonymous variants that disrupt messenger RNA structure are significantly constrained in the human population.GigaScience · 2021Article
- Molecular and Biochemical Techniques for Deciphering p53-MDM2 Regulatory Mechanisms.Biomolecules · 2020Review
- MDM2's dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities.Nucleic acids research · 2020Article
- Review
- Shaping the regulation of the p53 mRNA tumour suppressor: the co-evolution of genetic signatures.BMC cancer · 2019Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.