Deltex E3 ubiquitin ligase 3L is a protein that in humans is encoded by the DTX3L gene.[5] It functions as an ubiquitin ligase (E3),[6] and is over-expressed in chemotherapy-resistant lymphomas.[7] It is a member of the DTX family of proteins.[8] 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[9]), a gene related to the risk of B-cell lymphoma. and was originally named BBAP (B-lymphoma- and BAL-associated protein).[6]
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.[10] DTX3L has a long N-terminus domain distinct from other DTX-family proteins that allows it form dimers with itself and other proteins.[8] It has been found to be up-regulated by METTL3.[8]
Function
editDTX3L functions as an ubiquitin ligase or E3.[6] 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.[11] Along with all other known DTX-family proteins (as of 2023), DTX3L is involved in the regulation of Notch signaling.[8]
DTX3L also plays a role in DNA damage repair,[8] which has been associated with its ability to selectively mono-ubiquitylate (bind one ubiquitin to) histone H4.[7][8] It helps to protect cells exposed to DNA damaging agents.[7]
DTX3L can form a complex with PARP9.[12] 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.[12] This can help to control viral infection.[12] PARP9 can also affect DXT3L's function in DNA damage repair.[8] The DXT3L-PARP9 complex mediates mono-ADP-ribosylation of ubiquitin; this prevents it from being conjugated[13] and inhibits DXT3L's function as an ubiquitin ligase.[8] The NAD+ dependent binding of PARP9 to poly-ADP-ribose, instead, enhances the activity of DXT3L as a ubiquitin ligase.[8][why?] DTX3L can also form a complex with DTX1.[8]
DTX3L also affects signaling by inhibiting the sorting of the G-protein coupled receptor CXCR4 through the endosomes to degradation in the lysosomes.[14] When CXCR4 is activated, DXT3L localizes to early endosomes and inhibits the E3 ubiquitin ligase atrophin-1 interacting protein 4.[14] This reduces the extent to which the protein ESCRT-0 is ubiquitinated, which reduces its ability to sort CXCR4 into the lysosomes.[14] The implications of this effect (as of 2023) in cancer biology are unknown.[8]
References
edit- ^ a b c GRCh38: Ensembl release 89: ENSG00000163840 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000049502 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "DTX3L". National Center for Biotechnology Information. National Library of Medicine. Retrieved 2017-03-26.
- ^ a b c 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. doi:10.1074/jbc.M301157200. PMID 12670957.
- ^ a b c 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. doi:10.1016/j.molcel.2009.08.019. PMC 2913878. PMID 19818714.
- ^ a b c d e f g h i j k 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. doi:10.3390/cells12131680. ISSN 2073-4409. PMC 10340142. PMID 37443713.
- ^ "Symbol report for PARP9". HUGO Gene Nomenclature Committee. Retrieved 2024-07-20.
- ^ Juszczynski P, Kutok JL, Li C, Mitra J, Aguiar RC, Shipp MA (2006). "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. doi:10.1128/MCB.02351-05. PMC 1592708. PMID 16809771.
- ^ Nandi D, Tahiliani P, Kumar A, Chandu D (March 2006). "The ubiquitin-proteasome system". Journal of Biosciences. 31 (1): 137–155. doi:10.1007/BF02705243. PMID 16595883. S2CID 21603835.
- ^ a b c 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. 16 (12): 1215–1227. doi:10.1038/ni.3279. ISSN 1529-2916. PMC 4653074. PMID 26479788.
- ^ 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. doi:10.1016/j.molcel.2017.04.028. ISSN 1097-2765. PMC 5556935. PMID 28525742.
- ^ a b c 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. doi:10.1091/mbc.E13-10-0612. PMC 4055268. PMID 24790097.
Further reading
edit- Wilting SM, de Wilde J, Meijer CJ, Berkhof J, Yi Y, van Wieringen WN, Braakhuis BJ, Meijer GA, Ylstra B, Snijders PJ, Steenbergen RD (2008). "Integrated genomic and transcriptional profiling identifies chromosomal loci with altered gene expression in cervical cancer". Genes Chromosomes Cancer. 47 (10): 890–905. doi:10.1002/gcc.20590. PMC 2733213. PMID 18618715.
- Obiero J, Walker JR, Dhe-Paganon S (2012). "Fold of the conserved DTC domain in Deltex proteins". Proteins. 80 (5): 1495–9. doi:10.1002/prot.24054. PMID 22411408. S2CID 40043949.
- Yan Q, Xu R, Zhu L, Cheng X, Wang Z, Manis J, Shipp MA (2013). "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. doi:10.1128/MCB.00990-12. PMC 3571337. PMID 23230272.
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