Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCBN5LF)

• DOT Name: RNA polymerase II elongation factor ELL (ELL)
• Synonyms: Eleven-nineteen lysine-rich leukemia protein
• Gene Name: ELL
• Related Disease:
  Acute monocytic leukemia
  Adult acute monocytic leukemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Chronic myelomonocytic leukaemia
  Chronic myelomonocytic leukemia
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Von hippel-lindau disease
  Coronary heart disease
  Acute leukaemia
  Acute myelogenous leukaemia
  leukaemia
  Leukemia
• UniProt ID: ELL_HUMAN
• PDB ID: 2DOA
• Pfam ID: PF10390 ; PF07303
• Sequence:
  MAALKEDRSYGLSCGRVSDGSKVSVFHVKLTDSALRAFESYRARQDSVSLRPSIRFQGSQ
  GHISIPQPDCPAEARTFSFYLSNIGRDNPQGSFDCIQQYVSSHGEVHLDCLGSIQDKITV
  CATDDSYQKARQSMAQAEEETRSRSAIVIKAGGRYLGKKVQFRKPAPGATDAVPSRKRAT
  PINLASAIRKSGASAVSGGSGVSQRPFRDRVLHLLALRPYRKAELLLRLQKDGLTQADKD
  ALDGLLQQVANMSAKDGTCTLQDCMYKDVQKDWPGYSEGDQQLLKRVLVRKLCQPQSTGS
  LLGDPAASSPPGERGRSASPPQKRLQPPDFIDPLANKKPRISHFTQRAQPAVNGKLGVPN
  GREALLPTPGPPASTDTLSSSTHLPPRLEPPRAHDPLADVSNDLGHSGRDCEHGEAAAPA
  PTVRLGLPLLTDCAQPSRPHGSPSRSKPKKKSKKHKDKERAAEDKPRAQLPDCAPATHAT
  PGAPADTPGLNGTCSVSSVPTSTSETPDYLLKYAAISSSEQRQSYKNDFNAEYSEYRDLH
  ARIERITRRFTQLDAQLRQLSQGSEEYETTRGQILQEYRKIKKTNTNYSQEKHRCEYLHS
  KLAHIKRLIAEYDQRQLQAWP
• Function: 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. Elongation factor component of the little elongation complex (LEC), a complex required to regulate small nuclear RNA (snRNA) gene transcription by RNA polymerase II and III. Specifically required for stimulating the elongation step of RNA polymerase II- and III-dependent snRNA gene transcription. ELL also plays an early role before its assembly into in the SEC complex by stabilizing RNA polymerase II recruitment/initiation and entry into the pause site. Required to stabilize the pre-initiation complex and early elongation.
• Tissue Specificity: Expressed in all tissues tested. Highest levels found in placenta, skeletal muscle, testis and peripheral blood leukocytes.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway:
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Tat-mediated HIV elongation arrest and recovery (R-HSA-167243)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  HIV elongation arrest and recovery (R-HSA-167287)
  Pausing and recovery of HIV elongation (R-HSA-167290)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  RNA polymerase II transcribes snRNA genes (R-HSA-6807505)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Genetic Variation	[1]
Adult acute monocytic leukemia	DISG6BLX	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Chronic myelomonocytic leukaemia	DISDN5P7	Strong	Genetic Variation	[5]
Chronic myelomonocytic leukemia	DISIL8UR	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[8]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Altered Expression	[9]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[10]
Acute leukaemia	DISDQFDI	Limited	Biomarker	[11]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[1]
leukaemia	DISS7D1V	Limited	Altered Expression	[12]
Leukemia	DISNAKFL	Limited	Altered Expression	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of RNA polymerase II elongation factor ELL (ELL).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RNA polymerase II elongation factor ELL (ELL).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of RNA polymerase II elongation factor ELL (ELL).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of RNA polymerase II elongation factor ELL (ELL).	[21]

5 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 RNA polymerase II elongation factor ELL (ELL).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of RNA polymerase II elongation factor ELL (ELL).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RNA polymerase II elongation factor ELL (ELL).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RNA polymerase II elongation factor ELL (ELL).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of RNA polymerase II elongation factor ELL (ELL).	[19]

References

• [1] A New Complex Karyotype Involving a KMT2A-r Variant Three-Way Translocation in a Rare Clinical Presentation of a Pediatric Patient with Acute Myeloid Leukemia.Cytogenet Genome Res. 2019;157(4):213-219. doi: 10.1159/000499640. Epub 2019 Apr 12.
• [2] Neonatal acute myeloid leukemia in an infant whose mother was exposed to diethylstilboestrol in utero.Pediatr Blood Cancer. 2009 Aug;53(2):220-2. doi: 10.1002/pbc.22040.
• [3] Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells.Biochem Biophys Res Commun. 2014 May 2;447(2):292-8. doi: 10.1016/j.bbrc.2014.03.138. Epub 2014 Apr 12.
• [4] Genetic variants of genes in the NER pathway associated with risk of breast cancer: A large-scale analysis of 14 published GWAS datasets in the DRIVE study.Int J Cancer. 2019 Sep 1;145(5):1270-1279. doi: 10.1002/ijc.32371. Epub 2019 May 13.
• [5] A novel variant form of MLL-ELL fusion transcript with t(11;19)(q23;p13.1) in chronic myelomonocytic leukemia transforming to acute myeloid leukemia.Cancer Genet Cytogenet. 2008 Jul 15;184(2):109-12. doi: 10.1016/j.cancergencyto.2008.04.001.
• [6] ELL targets c-Myc for proteasomal degradation and suppresses tumour growth.Nat Commun. 2016 Mar 24;7:11057. doi: 10.1038/ncomms11057.
• [7] Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice.PLoS One. 2013 Nov 18;8(11):e79542. doi: 10.1371/journal.pone.0079542. eCollection 2013.
• [8] Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia.J Endocrinol. 2017 Nov;235(2):123-136. doi: 10.1530/JOE-17-0112.
• [9] An RNA polymerase II elongation factor encoded by the human ELL gene.Science. 1996 Mar 29;271(5257):1873-6. doi: 10.1126/science.271.5257.1873.
• [10] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [11] ELL and EAF1 are Cajal body components that are disrupted in MLL-ELL leukemia.Mol Biol Cell. 2003 Apr;14(4):1517-28. doi: 10.1091/mbc.e02-07-0394.
• [12] AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia.Mol Cell. 2010 Feb 12;37(3):429-37. doi: 10.1016/j.molcel.2010.01.026.
• [13] 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.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [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.