Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects

Nat Commun. 2024 Apr 26;15(1):3301. doi: 10.1038/s41467-024-47670-1.


Diphthamide is a modified histidine residue unique for eukaryotic translation elongation factor 2 (eEF2), a key ribosomal protein. Loss of this evolutionarily conserved modification causes developmental defects through unknown mechanisms. In a patient with compound heterozygous mutations in Diphthamide Biosynthesis 1 (DPH1) and impaired eEF2 diphthamide modification, we observe multiple defects in neural crest (NC)-derived tissues. Knockin mice harboring the patient's mutations and Xenopus embryos with Dph1 depleted also display NC defects, which can be attributed to reduced proliferation in the neuroepithelium. DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation. Knockout of one p21 allele rescues the NC phenotypes in the knockin mice carrying the patient's mutations. These findings uncover an unexpected role for eEF2 as a transcriptional coactivator for p53 to induce p21 expression and NC defects, which is regulated by diphthamide modification.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21* / genetics
  • Cyclin-Dependent Kinase Inhibitor p21* / metabolism
  • Female
  • Gene Knock-In Techniques
  • Histidine* / analogs & derivatives*
  • Histidine* / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Minor Histocompatibility Antigens*
  • Mutation
  • Neural Crest* / metabolism
  • Peptide Elongation Factor 2* / genetics
  • Peptide Elongation Factor 2* / metabolism
  • Ribosomes / metabolism
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism
  • Tumor Suppressor Proteins*
  • Xenopus
  • Xenopus laevis


  • diphthamide
  • Tumor Suppressor Protein p53
  • Cyclin-Dependent Kinase Inhibitor p21
  • Peptide Elongation Factor 2
  • Histidine
  • DPH1 protein, human
  • CDKN1A protein, human
  • TP53 protein, human
  • Minor Histocompatibility Antigens
  • Tumor Suppressor Proteins