ArticleeLife2020
Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants.
Article in eLife, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 68 citations in OpenAlex.
- Review
- A Tale of Two Mechanisms: The p53 Modulator COTI-2 Is a Zn Metallochaperone.Drug development research · 2026Article
- TP53 mutation at codon 179 metabolically reprograms cancer cells to promote invasion.Cancer gene therapy · 2026Article
- Reactivation ofInternational journal of molecular sciences · 2026Article
- Evaluation of non-canonical p53 functions in DNA replication and recombination for variant classification.Cell death & disease · 2026Article
- Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network.Molecular cell · 2026Article
- Integrated molecular dynamics elucidation of TP53 H179 zinc-binding variants: genomic and structural characterization across NSCLC subtypes.Frontiers in bioinformatics · 2026Article
- Functional restoration of conformational (R175H) and contact (R273H) mutant p53 byFrontiers in bioinformatics · 2026Article
- Regulatory Role of Zinc in Acute Promyelocytic Leukemia: Cellular and Molecular Aspects with Therapeutic Implications.International journal of molecular sciences · 2025Review
- The TP53 tumor suppressor gene: From molecular biology to clinical investigations.Journal of internal medicine · 2025Review
- Bypassing the guardian: regulated cell death pathways in p53-mutant cancers.Cellular & molecular biology letters · 2025Review
- TP53: the unluckiest of genes?Cell death and differentiation · 2025Review
- Deciphering the safeguarding role of cysteine residues in p53 against HCommunications chemistry · 2025Article
- ComparativeProtein and peptide letters · 2025Article
- TP53 mutations in cancer: Molecular features and therapeutic opportunities (Review).International journal of molecular medicine · 2025Review
- GRAIL1 Stabilizes Misfolded Mutant p53 through a Ubiquitin Ligase-Independent, Chaperone Regulatory Function.Molecular cancer research : MCR · 2024Article
- Pyrimidine Triones as Potential Activators of p53 Mutants.Biomolecules · 2024Article
- Targeting bacterial nickel transport with aspergillomarasmine A suppresses virulence-associated Ni-dependent enzymes.Nature communications · 2024Article
- Review
- Review
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Missense mutations in the p53 DNA-binding domain (DBD) contribute to half of new cancer cases annually. Here we present a thermodynamic model that quantifies and links the major pathways by which mutations inactivate p53. We find that DBD possesses two unusual properties-one of the highest zinc affinities of any eukaryotic protein and extreme instability in the absence of zinc-which are predicted to poise p53 on the cusp of folding/unfolding in the cell, with a major determinant being available zinc concentration. We analyze the 20 most common tumorigenic p53 mutations and find that 80% impair zinc affinity, thermodynamic stability, or both. Biophysical, cell-based, and murine xenograft experiments demonstrate that a synthetic zinc metallochaperone rescues not only mutations that decrease zinc affinity, but also mutations that destabilize DBD without impairing zinc binding. The results suggest that zinc metallochaperones have the capability to treat 120,500 patients annually in the U.S.
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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.