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

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  • Yu Shi

    (Children’s Hospital of Chongqing Medical University, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders
    University of Delaware)

  • Daochao Huang

    (Children’s Hospital of Chongqing Medical University)

  • Cui Song

    (Children’s Hospital of Chongqing Medical University)

  • Ruixue Cao

    (Wenzhou Medical University)

  • Zhao Wang

    (Wenzhou Medical University)

  • Dan Wang

    (Children’s Hospital of Chongqing Medical University)

  • Li Zhao

    (Children’s Hospital of Chongqing Medical University)

  • Xiaolu Xu

    (University of Delaware)

  • Congyu Lu

    (University of Delaware)

  • Feng Xiong

    (Children’s Hospital of Chongqing Medical University)

  • Haowen Zhao

    (Children’s Hospital of Chongqing Medical University, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders
    Children’s Hospital of Chongqing Medical University)

  • Shuxiang Li

    (Children’s Hospital of Chongqing Medical University
    Children’s Hospital of Chongqing Medical University)

  • Quansheng Zhou

    (Children’s Hospital of Chongqing Medical University
    Children’s Hospital of Chongqing Medical University)

  • Shuyue Luo

    (Children’s Hospital of Chongqing Medical University)

  • Dongjie Hu

    (Children’s Hospital of Chongqing Medical University)

  • Yun Zhang

    (Children’s Hospital of Chongqing Medical University)

  • Cui Wang

    (Children’s Hospital of Chongqing Medical University)

  • Yiping Shen

    (Boston Children’s Hospital and Harvard Medical School)

  • Weiting Su

    (Chinese Academy of Science)

  • Yili Wu

    (Wenzhou Medical University)

  • Karl Schmitz

    (University of Delaware)

  • Shuo Wei

    (University of Delaware)

  • Weihong Song

    (Wenzhou Medical University)

Abstract

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.

Suggested Citation

  • Yu Shi & Daochao Huang & Cui Song & Ruixue Cao & Zhao Wang & Dan Wang & Li Zhao & Xiaolu Xu & Congyu Lu & Feng Xiong & Haowen Zhao & Shuxiang Li & Quansheng Zhou & Shuyue Luo & Dongjie Hu & Yun Zhang , 2024. "Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47670-1
    DOI: 10.1038/s41467-024-47670-1
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