Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTALC1YD)

• DOT Name: RNA polymerase II elongation factor ELL3 (ELL3)
• Gene Name: ELL3
• Related Disease:
  B-cell lymphoma
  Lymphoma
  Multiple sclerosis
• UniProt ID: ELL3_HUMAN
• Pfam ID: PF10390 ; PF07303
• Sequence:
  MEELQEPLRGQLRLCFTQAARTSLLLLRLNDAALRALQECQRQQVRPVIAFQGHRGYLRL
  PGPGWSCLFSFIVSQCCQEGAGGSLDLVCQRFLRSGPNSLHCLGSLRERLIIWAAMDSIP
  APSSVQGHNLTEDARHPESWQNTGGYSEGDAVSQPQMALEEVSVSDPLASNQGQSLPGSS
  REHMAQWEVRSQTHVPNREPVQALPSSASRKRLDKKRSVPVATVELEEKRFRTLPLVPSP
  LQGLTNQDLQEGEDWEQEDEDMDPRLEHSSSVQEDSESPSPEDIPDYLLQYRAIHSAEQQ
  HAYEQDFETDYAEYRILHARVGTASQRFIELGAEIKRVRRGTPEYKVLEDKIIQEYKKFR
  KQYPSYREEKRRCEYLHQKLSHIKGLILEFEEKNRGS
• Function: Enhancer-binding elongation factor that specifically binds enhancers in embryonic stem cells (ES cells), marks them, and is required for their future activation during stem cell specification. Does not only bind to enhancer regions of active genes, but also marks the enhancers that are in a poised or inactive state in ES cells and is required for establishing proper RNA polymerase II occupancy at developmentally regulated genes in a cohesin-dependent manner. Probably required for priming developmentally regulated genes for later recruitment of the super elongation complex (SEC), for transcriptional activation during differentiation. Required for recruitment of P-TEFb within SEC during differentiation. Probably preloaded on germ cell chromatin, suggesting that it may prime gene activation by marking enhancers as early as in the germ cells. Promoting epithelial-mesenchymal transition (EMT). Elongation factor component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. Component of the little elongation complex (LEC), a complex required to regulate small nuclear RNA (snRNA) gene transcription by RNA polymerase II and III.
• Tissue Specificity: Testis specific.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway: RNA polymerase II transcribes snRNA genes (R-HSA-6807505)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[1]
Lymphoma	DISN6V4S	Strong	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	RNA polymerase II elongation factor ELL3 (ELL3) affects the response to substance of Doxorubicin.	[10]
Topotecan	DMP6G8T	Approved	RNA polymerase II elongation factor ELL3 (ELL3) affects the response to substance of Topotecan.	[10]

6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of RNA polymerase II elongation factor ELL3 (ELL3).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of RNA polymerase II elongation factor ELL3 (ELL3).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RNA polymerase II elongation factor ELL3 (ELL3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of RNA polymerase II elongation factor ELL3 (ELL3).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of RNA polymerase II elongation factor ELL3 (ELL3).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of RNA polymerase II elongation factor ELL3 (ELL3).	[3]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RNA polymerase II elongation factor ELL3 (ELL3).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of RNA polymerase II elongation factor ELL3 (ELL3).	[9]

References

• [1] Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival.Mol Immunol. 2017 Nov;91:8-16. doi: 10.1016/j.molimm.2017.08.016. Epub 2017 Aug 31.
• [2] MS CD49d(+)CD154(+) Lymphocytes Reprogram Oligodendrocytes into Immune Reactive Cells Affecting CNS Regeneration.Cells. 2019 Nov 25;8(12):1508. doi: 10.3390/cells8121508.
• [3] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] 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.
• [10] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.