DTX3L Protein, Human

DTX3L Protein, an E3 ubiquitin-protein ligase, collaborates with ADP-ribosyltransferase PARP9 to fulfill key roles in DNA damage repair and interferon-mediated antiviral responses. It monoubiquitinates various histones, including H2A, H2B, H3, and H4, particularly at 'Lys-91' of histone H4 in response to DNA damage. The exact function of H4K91ub1 remains unclear but may serve as a licensing signal for additional histone H4 post-translational modifications. The PARP1-dependent PARP9-DTX3L-mediated ubiquitination facilitates the specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites. Additionally, DTX3L positively regulates STAT1-dependent interferon-stimulated gene transcription by monoubiquitinating histone H2B, promoting chromatin remodeling. Independently of its catalytic activity, DTX3L plays a crucial role in the sorting of CXCR4 from early endosomes to lysosomes, reducing E3 ligase ITCH activity and facilitating the ubiquitination of endosomal sorting complex required for transport (ESCRT-0) components HGS and STAM. Furthermore, in association with PARP9, DTX3L contributes to antiviral responses by mediating 'Lys-48'-linked ubiquitination of encephalomyocarditis virus (EMCV) and human rhinovirus (HRV) C3 proteases, leading to their proteasomal-mediated degradation. These diverse functions underscore the significance of DTX3L in regulating critical cellular processes.