View source for DTX3L

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Deltex E3 ubiquitin ligase 3L''' is a [[protein]] that in humans is encoded by the DTX3L [[gene]].<ref name="entrez">
{{cite web |title=DTX3L |url=https://www.ncbi.nlm.nih.gov/gene/151636 |access-date=2017-03-26 |website=[[National Center for Biotechnology Information]] |publisher=[[National Library of Medicine]]}}</ref> It functions as an [[ubiquitin ligase]] (E3),<ref name=":0">{{cite journal |vauthors=Takeyama K, Aguiar RC, Gu L, He C, Freeman GJ, Kutok JL, Aster JC, Shipp MA |year=2003 |title=The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity |journal=J. Biol. Chem. |volume=278 |issue=24 |pages=21930–7 |doi=10.1074/jbc.M301157200 |pmid=12670957 |doi-access=free}}</ref> and is over-expressed in chemotherapy-resistant lymphomas.<ref name=":1">{{cite journal |vauthors=Yan Q, Dutt S, Xu R, Graves K, Juszczynski P, Manis JP, Shipp MA |year=2009 |title=BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response |journal=Mol. Cell |volume=36 |issue=1 |pages=110–20 |doi=10.1016/j.molcel.2009.08.019 |pmc=2913878 |pmid=19818714}}</ref> It is a member of the DTX family of proteins.<ref name=":4">{{Cite journal |last1=Scalia |first1=Pierluigi |last2=Williams |first2=Stephen J. |last3=Suma |first3=Antonio |last4=Carnevale |first4=Vincenzo |date=2023-06-21 |title=The DTX Protein Family: An Emerging Set of E3 Ubiquitin Ligases in Cancer |journal=Cells |volume=12 |issue=13 |pages=1680 |doi=10.3390/cells12131680 |doi-access=free |issn=2073-4409 |pmid=37443713|pmc=10340142 }}</ref> 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 [[Poly (ADP-ribose) polymerase|PARP9]] (formerly BAL<ref>{{Cite web |title=Symbol report for PARP9 |url=https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:24118 |access-date=2024-07-20 |website=HUGO Gene Nomenclature Committee}}</ref>), a gene related to the risk of [[B-cell lymphoma]]. and was originally named BBAP (B-lymphoma- and BAL-associated protein).<ref name=":0" />
DTX3L and PARP9 are both located in the same 48kB region of the genome, and are both regulated by a [[Interferon gamma|IFN-γ]]-responsive bidirectional [[Promoter (genetics)|promoter]].<ref>{{cite journal |vauthors=Juszczynski P, Kutok JL, Li C, Mitra J, Aguiar RC, Shipp MA |title=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 |journal=Mol. Cell. Biol. |volume=26 |issue=14 |pages=5348–59 |year=2006 |pmid=16809771 |pmc=1592708 |doi=10.1128/MCB.02351-05 }}</ref> DTX3L has a long N-terminus domain distinct from other DTX-family proteins that allows it form [[Dimerization (chemistry)|dimers]] with itself and other proteins.<ref name=":4" /> It has been found to be up-regulated by [[METTL3]].<ref name=":4" />
==Function==
DTX3L functions as an [[E3 ubiquitin ligase|ubiquitin ligase]] or E3.<ref name=":0" /> These proteins bind to [[Ubiquitin-conjugating enzyme|ubiquitin-conjugating enzymes]] (E2s), and then transfer and bind the ubiquitin (activated by [[Ubiquitin-activating enzyme|E1s]]) from the E2s to the target protein.<ref name="Nandi">{{cite journal |vauthors=Nandi D, Tahiliani P, Kumar A, Chandu D |date=March 2006 |title=The ubiquitin-proteasome system |journal=Journal of Biosciences |volume=31 |issue=1 |pages=137–155 |doi=10.1007/BF02705243 |pmid=16595883 |s2cid=21603835}}</ref> Along with all other known DTX-family proteins (as of 2023), DTX3L is involved in the regulation of [[Notch signaling pathway|Notch signaling]].<ref name=":4" />
DTX3L also plays a role in DNA damage repair,<ref name=":4" /> which has been associated with its ability to selectively mono-ubiquitylate (bind one ubiquitin to) [[histone H4]].<ref name=":1" /><ref name=":4" /> It helps to protect cells exposed to DNA damaging agents.<ref name=":1" />
DTX3L can form a complex with [[Poly (ADP-ribose) polymerase|PARP9]].<ref name=":3">{{Cite journal |last1=Zhang |first1=Yong |last2=Mao |first2=Dailing |last3=Roswit |first3=William T. |last4=Jin |first4=Xiaohua |last5=Patel |first5=Anand C. |last6=Patel |first6=Dhara A. |last7=Agapov |first7=Eugene |last8=Wang |first8=Zhepeng |last9=Tidwell |first9=Rose M. |last10=Atkinson |first10=Jeffrey J. |last11=Huang |first11=Guangming |last12=McCarthy |first12=Ronald |last13=Yu |first13=Jinsheng |last14=Yun |first14=Nadezhda E. |last15=Paessler |first15=Slobodan |date=December 2015 |title=PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection |journal=Nature Immunology |language=en |volume=16 |issue=12 |pages=1215–1227 |doi=10.1038/ni.3279 |pmid=26479788 |pmc=4653074 |issn=1529-2916}}</ref> This complex functions as a ubiquitin ligase and ubiquitinates both host [[Histone H2B|histone H2BJ]], to promote expression of [[Interferon-stimulated gene|interferon-stimulated genes]], and viral [[3C protease]] to disrupt viral assembly.<ref name=":3" /> This can help to control viral infection.<ref name=":3" /> PARP9 can also affect DXT3L's function in DNA damage repair.<ref name=":4" /> The DXT3L-PARP9 complex mediates mono-[[ADP-ribosylation]] of ubiquitin; this prevents it from being conjugated<ref>{{Cite journal |last1=Yang |first1=Chun-Song |last2=Jividen |first2=Kasey |last3=Spencer |first3=Adam |last4=Dworak |first4=Natalia |last5=Ni |first5=Li |last6=Oostdyk |first6=Luke T. |last7=Chatterjee |first7=Mandovi |last8=Kusmider |first8=Beata |last9=Reon |first9=Brian |last10=Parlak |first10=Mahmut |last11=Gorbunova |first11=Vera |last12=Abbas |first12=Tarek |last13=Jeffery |first13=Erin |last14=Sherman |first14=Nicholas E. |last15=Paschal |first15=Bryce M. |date=2017-05-18 |title=Ubiquitin Modification by the E3 Ligase/ADP-ribosyltransferase Dtx3L/Parp9 |journal=Molecular Cell |volume=66 |issue=4 |pages=503–516.e5 |doi=10.1016/j.molcel.2017.04.028 |issn=1097-2765 |pmc=5556935 |pmid=28525742}}</ref> and inhibits DXT3L's function as an ubiquitin ligase.<ref name=":4" /> The [[NAD+]] dependent binding of PARP9 to [[Poly (ADP-ribose) polymerase|poly-ADP-ribose]], instead, enhances the activity of DXT3L as a ubiquitin ligase.<ref name=":4" />{{Why|date=July 2024}} DTX3L can also form a complex with [[DTX1]].<ref name=":4" />
DTX3L also affects signaling by inhibiting the sorting of the [[G protein-coupled receptor|G-protein coupled receptor]] [[CXCR4]] through the [[Endosome|endosomes]] to degradation in the [[Lysosome|lysosomes]].<ref name=":2">{{cite journal |vauthors=Holleman J, Marchese A |year=2014 |title=The ubiquitin ligase deltex-3l regulates endosomal sorting of the G protein-coupled receptor CXCR4 |journal=Mol. Biol. Cell |volume=25 |issue=12 |pages=1892–904 |doi=10.1091/mbc.E13-10-0612 |pmc=4055268 |pmid=24790097}}</ref> When CXCR4 is activated, DXT3L [[Protein localization|localizes]] to early endosomes and inhibits the E3 ubiquitin ligase [[atrophin-1 interacting protein 4]].<ref name=":2" /> This reduces the extent to which the protein [[ESCRT|ESCRT-0]] is ubiquitinated, which reduces its ability to sort CXCR4 into the lysosomes.<ref name=":2" /> The implications of this effect (as of 2023) in cancer biology are unknown.<ref name=":4" />
== References ==
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== Further reading ==
{{refbegin | 2}}
*{{cite journal |vauthors=Wilting SM, de Wilde J, Meijer CJ, Berkhof J, Yi Y, van Wieringen WN, Braakhuis BJ, Meijer GA, Ylstra B, Snijders PJ, Steenbergen RD |title=Integrated genomic and transcriptional profiling identifies chromosomal loci with altered gene expression in cervical cancer |journal=Genes Chromosomes Cancer |volume=47 |issue=10 |pages=890–905 |year=2008 |pmid=18618715 |pmc=2733213 |doi=10.1002/gcc.20590 }}
*{{cite journal |vauthors=Obiero J, Walker JR, Dhe-Paganon S |title=Fold of the conserved DTC domain in Deltex proteins |journal=Proteins |volume=80 |issue=5 |pages=1495–9 |year=2012 |pmid=22411408 |doi=10.1002/prot.24054 |s2cid=40043949 }}
*{{cite journal |vauthors=Yan Q, Xu R, Zhu L, Cheng X, Wang Z, Manis J, Shipp MA |title=BAL1 and its partner E3 ligase, BBAP, link Poly(ADP-ribose) activation, ubiquitylation, and double-strand DNA repair independent of ATM, MDC1, and RNF8 |journal=Mol. Cell. Biol. |volume=33 |issue=4 |pages=845–57 |year=2013 |pmid=23230272 |pmc=3571337 |doi=10.1128/MCB.00990-12 }}
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