Department of Clinical Laboratory, 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, 136 Zhongshan 2nd Rd, Chongqing, 400014, China.
Department of Biological Sciences, University of Delaware, Newark, DE, 19716, USA.
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.
二氢尿嘧啶是真核翻译延伸因子 2（eEF2）的一个独特的组氨酸残基，eEF2 是一种关键的核糖体蛋白。这种进化上保守的修饰缺失通过未知的机制导致发育缺陷。在 Diphthamide Biosynthesis 1（DPH1）复合杂合突变和 eEF2 二氢尿嘧啶修饰受损的患者中，我们观察到神经嵴（NC）衍生组织的多种缺陷。携带患者突变的基因敲入小鼠和 Xenopus 胚胎中 Dph1 耗尽也显示出 NC 缺陷，这可归因于神经上皮细胞增殖减少。DPH1 耗竭促进 eEF2 从核糖体上解离，并与 p53 结合，从而促进细胞周期抑制剂 p21 的转录，导致增殖受到抑制。敲除一个 p21 等位基因可挽救携带患者突变的基因敲入小鼠中的 NC 表型。这些发现揭示了 eEF2 作为 p53 的转录共激活因子的意外作用，可诱导 p21 表达和 NC 缺陷，其受二氢尿嘧啶修饰调节。
