DPH3 (diphthamide biosynthesis 3) encodes an essential enzyme required for diphthamide synthesis, a critical post-translational modification of eukaryotic translation elongation factor 2 (eEF2) that ensures reading-frame fidelity during protein translation 1. DPH3 functions as an electron donor and iron chaperone, maintaining the iron-sulfur clusters in DPH1-DPH2 complexes in their active, reduced state by donating iron atoms to reform degraded [4Fe-4S] clusters [UniProt]. The protein also associates with the elongator complex and contributes to tRNA wobble base modifications [UniProt]. Clinically, DPH3 has significant relevance in cancer, particularly skin cancers. Frequent somatic mutations occur in the DPH3 promoter region in melanoma (10%), basal cell carcinoma (42-49%), and squamous cell carcinoma (39%), displaying typical UV-signature mutations 234. These promoter mutations show increased activity in reporter assays, though their functional impact on transcription remains unclear 2. Additionally, DPH3 promotes melanoma cell migration and metastasis through AKT signaling pathway activation 5. The gene's involvement in diphthamide synthesis also makes it relevant for understanding viral infections, as diphthamide may restrict viral propagation 1.