DTX3L explained

Deltex E3 ubiquitin ligase 3L is a protein that in humans is encoded by the DTX3L gene.^[1] It functions as an ubiquitin ligase (E3),^[2] and is over-expressed in chemotherapy-resistant lymphomas.^[3] It is a member of the DTX family of proteins.^[4] 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^[5]), 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.^[6] 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.^[7] 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.^[8] 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^[9] 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.^[10] 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.

Further reading

• Wilting SM, de Wilde J, Meijer CJ, Berkhof J, Yi Y, van Wieringen WN, Braakhuis BJ, Meijer GA, Ylstra B, Snijders PJ, Steenbergen RD . Integrated genomic and transcriptional profiling identifies chromosomal loci with altered gene expression in cervical cancer . Genes Chromosomes Cancer . 47 . 10 . 890–905 . 2008 . 18618715 . 2733213 . 10.1002/gcc.20590 .
• Obiero J, Walker JR, Dhe-Paganon S . Fold of the conserved DTC domain in Deltex proteins . Proteins . 80 . 5 . 1495–9 . 2012 . 22411408 . 10.1002/prot.24054 . 40043949 .
• Yan Q, Xu R, Zhu L, Cheng X, Wang Z, Manis J, Shipp MA . BAL1 and its partner E3 ligase, BBAP, link Poly(ADP-ribose) activation, ubiquitylation, and double-strand DNA repair independent of ATM, MDC1, and RNF8 . Mol. Cell. Biol. . 33 . 4 . 845–57 . 2013 . 23230272 . 3571337 . 10.1128/MCB.00990-12 .

Notes and References

1. Web site: DTX3L . 2017-03-26 . . National Library of Medicine.
2. Takeyama K, Aguiar RC, Gu L, He C, Freeman GJ, Kutok JL, Aster JC, Shipp MA . 2003 . The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity . J. Biol. Chem. . 278 . 24 . 21930–7 . 10.1074/jbc.M301157200 . 12670957 . free.
3. Yan Q, Dutt S, Xu R, Graves K, Juszczynski P, Manis JP, Shipp MA . 2009 . BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response . Mol. Cell . 36 . 1 . 110–20 . 10.1016/j.molcel.2009.08.019 . 2913878 . 19818714.
4. Scalia . Pierluigi . Williams . Stephen J. . Suma . Antonio . Carnevale . Vincenzo . 2023-06-21 . The DTX Protein Family: An Emerging Set of E3 Ubiquitin Ligases in Cancer . Cells . 12 . 13 . 1680 . 10.3390/cells12131680 . free . 2073-4409 . 37443713. 10340142 .
5. Web site: Symbol report for PARP9 . 2024-07-20 . HUGO Gene Nomenclature Committee.
6. Juszczynski P, Kutok JL, Li C, Mitra J, Aguiar RC, Shipp MA . BAL1 and BBAP are regulated by a gamma interferon-responsive bidirectional promoter and are overexpressed in diffuse large B-cell lymphomas with a prominent inflammatory infiltrate . Mol. Cell. Biol. . 26 . 14 . 5348–59 . 2006 . 16809771 . 1592708 . 10.1128/MCB.02351-05 .
7. Nandi D, Tahiliani P, Kumar A, Chandu D . March 2006 . The ubiquitin-proteasome system . Journal of Biosciences . 31 . 1 . 137–155 . 10.1007/BF02705243 . 16595883 . 21603835.
8. Zhang . Yong . Mao . Dailing . Roswit . William T. . Jin . Xiaohua . Patel . Anand C. . Patel . Dhara A. . Agapov . Eugene . Wang . Zhepeng . Tidwell . Rose M. . Atkinson . Jeffrey J. . Huang . Guangming . McCarthy . Ronald . Yu . Jinsheng . Yun . Nadezhda E. . Paessler . Slobodan . December 2015 . PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection . Nature Immunology . en . 16 . 12 . 1215–1227 . 10.1038/ni.3279 . 26479788 . 4653074 . 1529-2916.
9. Yang . Chun-Song . Jividen . Kasey . Spencer . Adam . Dworak . Natalia . Ni . Li . Oostdyk . Luke T. . Chatterjee . Mandovi . Kusmider . Beata . Reon . Brian . Parlak . Mahmut . Gorbunova . Vera . Abbas . Tarek . Jeffery . Erin . Sherman . Nicholas E. . Paschal . Bryce M. . 2017-05-18 . Ubiquitin Modification by the E3 Ligase/ADP-ribosyltransferase Dtx3L/Parp9 . Molecular Cell . 66 . 4 . 503–516.e5 . 10.1016/j.molcel.2017.04.028 . 1097-2765 . 5556935 . 28525742.
10. Holleman J, Marchese A . 2014 . The ubiquitin ligase deltex-3l regulates endosomal sorting of the G protein-coupled receptor CXCR4 . Mol. Biol. Cell . 25 . 12 . 1892–904 . 10.1091/mbc.E13-10-0612 . 4055268 . 24790097.