DTX3L (deltex E3 ubiquitin ligase 3L) is a multi-domain E3 ubiquitin ligase with diverse roles in DNA damage repair, antiviral immunity, and cancer biology 1. In DNA repair, DTX3L associates with PARP9 to monoubiquitinate histones H2A, H2B, H3, and H4, mediating H4K91 ubiquitination that facilitates recruitment of repair factors 53BP1, RAP80, and BRCA1 to damage sites 2. DTX3L regulates DNA repair pathway choice by ubiquitinating TIRR, promoting its nuclear export and degradation to modulate 53BP1 activity and PARP inhibitor sensitivity 2. In antiviral responses, DTX3L promotes interferon-stimulated gene transcription by monoubiquitinating histone H2B and mediates degradation of viral proteases through K48-linked ubiquitination 3. The enzyme's activity is regulated by NAD+ concentration and binding partners 1. In lymphatic development, DTX3L functions downstream of Piezo1-mediated mechanotransduction to promote sprouting through Notch downregulation 4. Clinically, DTX3L is dysregulated in multiple cancers including esophageal squamous cell carcinoma and prostate cancer, promoting tumorigenesis through effects on proliferation and migration 5. DTX3L mediates FPN1 degradation during viral infection, disrupting iron homeostasis and suppressing antiviral defenses 6, and regulates muscle fibrosis in cancer cachexia through Runx2 ubiquitination 7.