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

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	Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects
	Shi, Y; Huang, DC; Song, C; Cao, RX; Wang, Z; Wang, D; Zhao, L; Xu, XL; Lu, CY; Xiong, F; Zhao, HW; Li, SX; Zhou, QS; Luo, SY; Hu, DJ; Zhang, Y; Wang, C; Shen, YP; Su, WT; Wu, YL; Schmitz, K; Wei, S; Song, WH
	2024
发表期刊	NATURE COMMUNICATIONS
ISSN	2041-1723
卷号	15 期号:1
摘要	iphthamide 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. Rare disease DEDSSH1-associated DPH1 mutations impair eEF2 diphthamide modification that leads to eEF2 as a transcriptional coactivator for p53 to enhance expression of the cell proliferation inhibitor p21, resulting in birth defects.
收录类别	sci
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/14269
专题	遗传资源与进化国家重点实验室_保护遗传学(细胞库)
推荐引用方式 GB/T 7714	Shi, Y,Huang, DC,Song, C,et al. Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects[J]. NATURE COMMUNICATIONS,2024,15(1).
APA	Shi, Y.,Huang, DC.,Song, C.,Cao, RX.,Wang, Z.,...&Song, WH.(2024).Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects.NATURE COMMUNICATIONS,15(1).
MLA	Shi, Y,et al."Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects".NATURE COMMUNICATIONS 15.1(2024).

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