Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH5IL2A)

• DOT Name: DNA-directed RNA polymerases I, II, and III subunit RPABC1 (POLR2E)
• Synonyms: RNA polymerases I, II, and III subunit ABC1; DNA-directed RNA polymerase II 23 kDa polypeptide; DNA-directed RNA polymerase II subunit E; RPB5 homolog; XAP4
• Gene Name: POLR2E
• Related Disease:
  Advanced cancer
  Carcinoma of esophagus
  Carcinoma of liver and intrahepatic biliary tract
  Cervical cancer
  Cervical carcinoma
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Interstitial cystitis
  Liver cancer
  Neoplasm of esophagus
  Prostate cancer
  Prostate carcinoma
  Thyroid gland papillary carcinoma
• UniProt ID: RPAB1_HUMAN
• PDB ID: 5IY6; 5IY7; 5IY8; 5IY9; 5IYA; 5IYB; 5IYC; 5IYD; 6DRD; 6O9L; 6XRE; 7A6H; 7AE1; 7AE3; 7AEA; 7AST; 7D58; 7D59; 7DN3; 7DU2; 7FJI; 7FJJ; 7LBM; 7OB9; 7OBA; 7OBB; 7VBA; 7VBB; 7VBC; 8A43; 8ITY; 8IUE; 8IUH
• Pfam ID: PF01191 ; PF03871
• Sequence:
  MDDEEETYRLWKIRKTIMQLCHDRGYLVTQDELDQTLEEFKAQSGDKPSEGRPRRTDLTV
  LVAHNDDPTDQMFVFFPEEPKVGIKTIKVYCQRMQEENITRALIVVQQGMTPSAKQSLVD
  MAPKYILEQFLQQELLINITEHELVPEHVVMTKEEVTELLARYKLRENQLPRIQAGDPVA
  RYFGIKRGQVVKIIRPSETAGRYITYRLVQ
• Function: DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2E/RPABC1 is part of the lower jaw surrounding the central large cleft and thought to grab the incoming DNA template.
• KEGG Pathway:
  R. polymerase (hsa03020)
  Nucleotide excision repair (hsa03420)
  Cytosolic D.-sensing pathway (hsa04623)
  Huntington disease (hsa05016)
• Reactome Pathway:
  Formation of the Early Elongation Complex (R-HSA-113418)
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of the HIV-1 Early Elongation Complex (R-HSA-167158)
  RNA Pol II CTD phosphorylation and interaction with CE during HIV infection (R-HSA-167160)
  HIV Transcription Initiation (R-HSA-167161)
  RNA Polymerase II HIV Promoter Escape (R-HSA-167162)
  Transcription of the HIV genome (R-HSA-167172)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Abortive elongation of HIV-1 transcript in the absence of Tat (R-HSA-167242)
  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)
  Viral Messenger RNA Synthesis (R-HSA-168325)
  Cytosolic sensors of pathogen-associated DNA (R-HSA-1834949)
  MicroRNA (miRNA) biogenesis (R-HSA-203927)
  NoRC negatively regulates rRNA expression (R-HSA-427413)
  B-WICH complex positively regulates rRNA expression (R-HSA-5250924)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  PIWI-interacting RNA (piRNA) biogenesis (R-HSA-5601884)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)
  Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  FGFR2 alternative splicing (R-HSA-6803529)
  RNA polymerase II transcribes snRNA genes (R-HSA-6807505)
  mRNA Capping (R-HSA-72086)
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA Splicing - Minor Pathway (R-HSA-72165)
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  RNA Polymerase I Promoter Escape (R-HSA-73772)
  RNA Polymerase II Promoter Escape (R-HSA-73776)
  RNA Polymerase II Transcription Pre-Initiation And Promoter Opening (R-HSA-73779)
  RNA Polymerase III Chain Elongation (R-HSA-73780)
  RNA Polymerase I Transcription Termination (R-HSA-73863)
  RNA Polymerase III Transcription Termination (R-HSA-73980)
  RNA Polymerase III Abortive And Retractive Initiation (R-HSA-749476)
  RNA Polymerase II Transcription Initiation (R-HSA-75953)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  RNA Polymerase II Transcription Initiation And Promoter Clearance (R-HSA-76042)
  RNA Polymerase III Transcription Initiation From Type 1 Promoter (R-HSA-76061)
  RNA Polymerase III Transcription Initiation From Type 2 Promoter (R-HSA-76066)
  RNA Polymerase III Transcription Initiation From Type 3 Promoter (R-HSA-76071)
  RNA Pol II CTD phosphorylation and interaction with CE (R-HSA-77075)
  Signaling by FGFR2 IIIa TM (R-HSA-8851708)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Inhibition of DNA recombination at telomere (R-HSA-9670095)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Carcinoma of esophagus	DISS6G4D	Strong	Genetic Variation	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Genetic Variation	[1]
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[1]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[1]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Interstitial cystitis	DIS7CAJA	Strong	Biomarker	[4]
Liver cancer	DISDE4BI	Strong	Genetic Variation	[1]
Neoplasm of esophagus	DISOLKAQ	Strong	Genetic Variation	[1]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[1]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC1 (POLR2E).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC1 (POLR2E).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC1 (POLR2E).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC1 (POLR2E).	[8]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC1 (POLR2E).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC1 (POLR2E).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC1 (POLR2E).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC1 (POLR2E).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC1 (POLR2E).	[13]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC1 (POLR2E).	[14]

References

• [1] The POLR2E rs3787016 polymorphism is strongly associated with the risk of female breast and cervical cancer.Pathol Res Pract. 2019 May;215(5):1061-1065. doi: 10.1016/j.prp.2019.02.015. Epub 2019 Feb 27.
• [2] Long noncoding RNAs POLR2E rs3787016 C/T and HULC rs7763881 A/C polymorphisms are associated with decreased risk of esophageal cancer.Tumour Biol. 2015 Aug;36(8):6401-8. doi: 10.1007/s13277-015-3328-z. Epub 2015 Mar 31.
• [3] Down-regulation of retinol binding protein 5 is associated with aggressive tumor features in hepatocellular carcinoma.J Cancer Res Clin Oncol. 2007 Dec;133(12):929-36. doi: 10.1007/s00432-007-0230-0. Epub 2007 May 12.
• [4] RMP promotes venous metastases of hepatocellular carcinoma through promoting IL-6 transcription.Oncogene. 2015 Mar 19;34(12):1575-83. doi: 10.1038/onc.2014.84. Epub 2014 Apr 7.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [9] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [10] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [11] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [14] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.