E3 ubiquitin-protein ligase which, in association with ADP-ribosyltransferase PARP9, plays a role in DNA damage repair and in interferon-mediated antiviral responses (PubMed:12670957, PubMed:19818714, PubMed:26479788, PubMed:23230272). Monoubiquitinates several histones, including histone H2A, H2B, H3 and H4 (PubMed:28525742). In response to DNA damage, mediates monoubiquitination of 'Lys-91' of histone H4 (H4K91ub1) (PubMed:19818714). 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) (PubMed:19818714). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (PubMed:23230272). 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 (PubMed:26479788). 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 (PubMed:24790097). In addition, required for the recruitment of HGS and STAM to early endosomes (PubMed:24790097). In association with PARP9, plays a role in antiviral responses by mediating 'Lys-48'-linked ubiquitination of encephalomyocarditis virus (EMCV) and human rhinovirus (HRV) C3 proteases and thus promoting their proteosomal-mediated degradation (PubMed:26479788). 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 (PubMed:12670957, PubMed:28525742). Can heterodimerize with DTX1, enhancing its ubiquitin ligase activity in vitro (PubMed:12670957). 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 (PubMed:12670957, PubMed:23230272, PubMed:26479788, PubMed:28525742). Forms a complex with STAT1 and PARP9 independently of IFNB1 or IFNG-mediated STAT1 'Tyr-701' phosphorylation (PubMed:26479788). Found in a complex with PARP9, STAT1 and H2BC9 (PubMed:26479788). Found in a complex with E3 ligase ITCH and ESCRT-0 components HGS and STAM (PubMed:24790097). Interacts (via C-terminus) with ITCH; the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity; the interaction is direct (PubMed:24790097). Interacts with HGS and STAM; the interaction brings together HGS and STAM and promotes their recruitment to early endosomes (PubMed:24790097). (Microbial infection) Interacts with encephalomyocarditis virus (EMCV) C3 protease; the interaction results in C3 protease 'Lys-48'-linked ubiquitination. (Microbial infection) Interacts with human rhinovirus (HRV) C3 protease; the interaction results in C3 protease 'Lys-48'-linked ubiquitination. Translocates to the nucleus in response to IFNG or IFNB1 stimulation (PubMed:26479788). Localizes at sites of DNA damage in a PARP1-dependent manner (PubMed:23230272). Localization to early endosomes is increased upon CXCL12 stimulation where it co-localizes with ITCH, CXCL4, HGS and STAM (PubMed:24790097). A minor proportion localizes to lysosomes (PubMed:24790097). Induced by IFNG (PubMed:16809771, PubMed:26479788). Induced by IFNB1 (PubMed:26479788). Autoubiquitinated. Belongs to the Deltex family.