DTX3L

Deltex E3 ubiquitin ligase 3L is a protein that in humans is encoded by the DTX3L gene. It functions as an ubiquitin ligase (E3), and is over-expressed in chemotherapy-resistant lymphomas. It is a member of the DTX family of proteins. Among other roles it has a function in DNA damage repair.

It was discovered through two-hybrid screening during a search for binding partners of PARP9 (formerly BAL ), a gene related to the risk of B-cell lymphoma. and was originally named BBAP (B-lymphoma- and BAL-associated protein).

DTX3L and PARP9 are both located in the same 48kB region of the genome, and are both regulated by a IFN-γ-responsive bidirectional promoter. DTX3L has a long N-terminus domain distinct from other DTX-family proteins that allows it form dimers with itself and other proteins. It has been found to be up-regulated by METTL3.

Function
DTX3L functions as an ubiquitin ligase or E3. These proteins bind to ubiquitin-conjugating enzymes (E2s), and then transfer and bind the ubiquitin (activated by E1s) from the E2s to the target protein. Along with all other known DTX-family proteins (as of 2023), DTX3L is involved in the regulation of Notch signaling.

DTX3L also plays a role in DNA damage repair, which has been associated with its ability to selectively mono-ubiquitylate (bind one ubiquitin to) histone H4. It helps to protect cells exposed to DNA damaging agents.

DTX3L can form a complex with PARP9. This complex functions as a ubiquitin ligase and ubiquitinates both host histone H2BJ, to promote expression of interferon-stimulated genes, and viral 3C protease to disrupt viral assembly. This can help to control viral infection. PARP9 can also affect DXT3L's function in DNA damage repair. The DXT3L-PARP9 complex mediates mono-ADP-ribosylation of ubiquitin; this prevents it from being conjugated and inhibits DXT3L's function as an ubiquitin ligase. The NAD+ dependent binding of PARP9 to poly-ADP-ribose, instead, enhances the activity of DXT3L as a ubiquitin ligase. DTX3L can also form a complex with DTX1.

DTX3L also affects signaling by inhibiting the sorting of the G-protein coupled receptor CXCR4 through the endosomes to degradation in the lysosomes. When CXCR4 is activated, DXT3L localizes to early endosomes and inhibits the E3 ubiquitin ligase atrophin-1 interacting protein 4. This reduces the extent to which the protein ESCRT-0 is ubiquitinated, which reduces its ability to sort CXCR4 into the lysosomes. The implications of this effect (as of 2023) in cancer biology are unknown.