Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCCO2QZ)

DOT Name E3 ubiquitin-protein ligase DTX3L (DTX3L)
Synonyms EC 2.3.2.27; B-lymphoma- and BAL-associated protein; Protein deltex-3-like; RING-type E3 ubiquitin transferase DTX3L; Rhysin-2; Rhysin2
Gene Name DTX3L
Related Disease
B-cell lymphoma ( )
Glioma ( )
Metastatic prostate carcinoma ( )
Neoplasm ( )
Plasma cell myeloma ( )
Advanced cancer ( )
UniProt ID
DTX3L_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
3PG6
EC Number
2.3.2.27
Pfam ID
PF18102 ; PF21717 ; PF21718 ; PF13923
Sequence
MASHLRPPSPLLVRVYKSGPRVRRKLESYFQSSKSSGGGECTVSTQEHEAPGTFRVEFSE
RAAKERVLKKGEHQILVDEKPVPIFLVPTENSIKKNTRPQISSLTQSQAETPSGDMHQHE
GHIPNAVDSCLQKIFLTVTADLNCNLFSKEQRAYITTLCPSIRKMEGHDGIEKVCGDFQD
IERIHQFLSEQFLESEQKQQFSPSMTERKPLSQQERDSCISPSEPETKAEQKSNYFEVPL
PYFEYFKYICPDKINSIEKRFGVNIEIQESSPNMVCLDFTSSRSGDLEAARESFASEFQK
NTEPLKQECVSLADSKQANKFKQELNHQFTKLLIKEKGGELTLLGTQDDISAAKQKISEA
FVKIPVKLFAANYMMNVIEVDSAHYKLLETELLQEISEIEKRYDICSKVSEKGQKTCILF
ESKDRQVDLSVHAYASFIDAFQHASCQLMREVLLLKSLGKERKHLHQTKFADDFRKRHPN
VHFVLNQESMTLTGLPNHLAKAKQYVLKGGGMSSLAGKKLKEGHETPMDIDSDDSKAASP
PLKGSVSSEASELDKKEKGICVICMDTISNKKVLPKCKHEFCAPCINKAMSYKPICPTCQ
TSYGIQKGNQPEGSMVFTVSRDSLPGYESFGTIVITYSMKAGIQTEEHPNPGKRYPGIQR
TAYLPDNKEGRKVLKLLYRAFDQKLIFTVGYSRVLGVSDVITWNDIHHKTSRFGGPEMYG
YPDPSYLKRVKEELKAKGIE
Function
E3 ubiquitin-protein ligase which, in association with ADP-ribosyltransferase PARP9, plays a role in DNA damage repair and in interferon-mediated antiviral responses. Monoubiquitinates several histones, including histone H2A, H2B, H3 and H4. In response to DNA damage, mediates monoubiquitination of 'Lys-91' of histone H4 (H4K91ub1). The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 'Lys-20' methylation (H4K20me). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites. By monoubiquitinating histone H2B H2BC9/H2BJ and thereby promoting chromatin remodeling, positively regulates STAT1-dependent interferon-stimulated gene transcription and thus STAT1-mediated control of viral replication. Independently of its catalytic activity, promotes the sorting of chemokine receptor CXCR4 from early endosome to lysosome following CXCL12 stimulation by reducing E3 ligase ITCH activity and thus ITCH-mediated ubiquitination of endosomal sorting complex required for transport ESCRT-0 components HGS and STAM. In addition, required for the recruitment of HGS and STAM to early endosomes. In association with PARP9, plays a role in antiviral responses by mediating 'Lys-48'-linked ubiquitination of encephalomyocarditis virus (EMCV) and human rhinovirus (HRV) C3 proteases and thus promoting their proteasomal-mediated degradation.
KEGG Pathway
Notch sig.ling pathway (hsa04330 )
Reactome Pathway
Antigen processing (R-HSA-983168 )

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
B-cell lymphoma DISIH1YQ Strong Biomarker [1]
Glioma DIS5RPEH Strong Altered Expression [2]
Metastatic prostate carcinoma DISVBEZ9 Strong Biomarker [3]
Neoplasm DISZKGEW Strong Biomarker [3]
Plasma cell myeloma DIS0DFZ0 Strong Biomarker [4]
Advanced cancer DISAT1Z9 moderate Biomarker [5]
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⏷ Show the Full List of 6 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the methylation of E3 ubiquitin-protein ligase DTX3L (DTX3L). [6]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase DTX3L (DTX3L). [21]
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18 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [7]
Tretinoin DM49DUI Approved Tretinoin increases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [8]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [9]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [10]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [11]
Estradiol DMUNTE3 Approved Estradiol increases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [12]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [13]
Triclosan DMZUR4N Approved Triclosan increases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [14]
Hydroquinone DM6AVR4 Approved Hydroquinone decreases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [15]
Diethylstilbestrol DMN3UXQ Approved Diethylstilbestrol decreases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [16]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [17]
Nabiximols DMHKJ5I Phase 3 Nabiximols decreases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [18]
Belinostat DM6OC53 Phase 2 Belinostat decreases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [13]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [19]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [20]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [22]
Formaldehyde DM7Q6M0 Investigative Formaldehyde increases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [23]
methyl p-hydroxybenzoate DMO58UW Investigative methyl p-hydroxybenzoate decreases the expression of E3 ubiquitin-protein ligase DTX3L (DTX3L). [24]
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⏷ Show the Full List of 18 Drug(s)

References

1 HDAC1,2 inhibition impairs EZH2- and BBAP-mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma.Oncotarget. 2015 Mar 10;6(7):4863-87. doi: 10.18632/oncotarget.3120.
2 DTX3L is upregulated in glioma and is associated with glioma progression.Int J Mol Med. 2017 Aug;40(2):491-498. doi: 10.3892/ijmm.2017.3023. Epub 2017 Jun 13.
3 DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells.Mol Cancer. 2014 May 27;13:125. doi: 10.1186/1476-4598-13-125.
4 Effects of DTX3L on the cell proliferation, adhesion, and drug resistance of multiple myeloma cells.Tumour Biol. 2017 Jun;39(6):1010428317703941. doi: 10.1177/1010428317703941.
5 LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer.Elife. 2018 Jan 19;7:e31334. doi: 10.7554/eLife.31334.
6 Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
7 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
8 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
9 Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
10 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
11 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
12 Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
13 Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
14 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
15 Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
16 Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
17 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
18 Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis. Eur J Neurol. 2018 Jul;25(7):934-e70. doi: 10.1111/ene.13623. Epub 2018 Apr 16.
19 Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
20 Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
21 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
22 Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
23 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
24 Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.