Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG7IQ2V)

• DOT Name: DNA-directed RNA polymerases I, II, and III subunit RPABC3 (POLR2H)
• Synonyms: RNA polymerases I, II, and III subunit ABC3; DNA-directed RNA polymerase II subunit H; DNA-directed RNA polymerases I, II, and III 17.1 kDa polypeptide; RPB17; RPB8 homolog; hRPB8
• Gene Name: POLR2H
• UniProt ID: RPAB3_HUMAN
• PDB ID: 2F3I ; 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: PF03870
• Sequence:
  MAGILFEDIFDVKDIDPEGKKFDRVSRLHCESESFKMDLILDVNIQIYPVDLGDKFRLVI
  ASTLYEDGTLDDGEYNPTDDRPSRADQFEYVMYGKVYRIEGDETSTEAATRLSAYVSYGG
  LLMRLQGDANNLHGFEVDSRVYLLMKKLAF
• 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.
• 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

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC3 (POLR2H).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC3 (POLR2H).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC3 (POLR2H).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC3 (POLR2H).	[4]
Marinol	DM70IK5	Approved	Marinol decreases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC3 (POLR2H).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC3 (POLR2H).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC3 (POLR2H).	[8]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC3 (POLR2H).	[9]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of DNA-directed RNA polymerases I, II, and III subunit RPABC3 (POLR2H).	[10]

1 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 DNA-directed RNA polymerases I, II, and III subunit RPABC3 (POLR2H).	[5]

References

• [1] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 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.
• [5] 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.
• [6] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [8] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [9] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [10] 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.