E3 ubiquitin-protein ligase which, in association with ADP-ribosyltransferase PARP9, plays a role in DNA damage repair and in interferon-mediated antiviral responses. Monoubiquitinates several histones, including histone H2A, H2B, H3 and H4. In response to DNA damage, mediates monoubiquitination of 'Lys-91' of histone H4 (H4K91ub1). The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 'Lys-20' methylation (H4K20me). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites. By monoubiquitinating histone H2B H2BC9/H2BJ and thereby promoting chromatin remodeling, positively regulates STAT1-dependent interferon-stimulated gene transcription and thus STAT1-mediated control of viral replication. Independently of its catalytic activity, promotes the sorting of chemokine receptor CXCR4 from early endosome to lysosome following CXCL12 stimulation by reducing E3 ligase ITCH activity and thus ITCH-mediated ubiquitination of endosomal sorting complex required for transport ESCRT-0 components HGS and STAM. In addition, required for the recruitment of HGS and STAM to early endosomes. S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine. Binding to PARP9 enhances DTX3L catalytic activity. Protein modification; protein ubiquitination. Homodimer and heterodimer. Can heterodimerize with DTX1, enhancing its ubiquitin ligase activity in vitro. Interacts (via N-terminus) with ADP ribosyltransferase PARP9/BAL1 (via PARP catalytic domain) forming a stable complex; the interaction is required to activate PARP9 but is dispensable for DTX3L catalytic activity. Forms a complex with STAT1 and PARP9 independently of IFNB1 or IFNG-mediated STAT1 'Tyr-701' phosphorylation. Found in a complex with PARP9, STAT1 and H2BC9. Found in a complex with E3 ligase ITCH and ESCRT-0 components HGS and STAM. Interacts (via C-terminus) with ITCH; the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity; the interaction is direct. Interacts with HGS and STAM; the interaction brings together HGS and STAM and promotes their recruitment to early endosomes. Translocates to the nucleus in response to IFNG or IFNB1 stimulation. Localizes at sites of DNA damage in a PARP1-dependent manner. Localization to early endosomes is increased upon CXCL12 stimulation where it co-localizes with ITCH, CXCL4, HGS and STAM. A minor proportion localizes to lysosomes. Developmentally regulated. Expressed prominently in the thymus and specific regions of the brain, and more weakly expressed in the gut. In adults, highly expressed in the thymus and intestine. Autoubiquitinated. Belongs to the Deltex family.