Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW7RZ18)

• DOT Name: DNA-directed RNA polymerase II subunit RPB4 (POLR2D)
• Synonyms: RNA polymerase II subunit B4; DNA-directed RNA polymerase II subunit D; RNA polymerase II 16 kDa subunit; RPB16
• Gene Name: POLR2D
• Related Disease:
  Cervical Intraepithelial neoplasia
  Matthew-Wood syndrome
  Pancreatic adenocarcinoma
• UniProt ID: RPB4_HUMAN
• PDB ID: 2C35; 5IY6; 5IY7; 5IY8; 5IY9; 5IYA; 5IYB; 5IYC; 5IYD; 6DRD; 6O9L; 6XRE; 7LBM
• Pfam ID: PF03874
• Sequence:
  MAAGGSDPRAGDVEEDASQLIFPKEFETAETLLNSEVHMLLEHRKQQNESAEDEQELSEV
  FMKTLNYTARFSRFKNRETIASVRSLLLQKKLHKFELACLANLCPETAEESKALIPSLEG
  RFEDEELQQILDDIQTKRSFQY
• Function: Core component of RNA polymerase II (Pol II), a DNA-dependent RNA polymerase which synthesizes mRNA precursors and many functional non-coding RNAs using the four ribonucleoside triphosphates as substrates. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. POLR2D/RPB4 is part of a subcomplex with POLR2G/RPB7 that binds to a pocket formed by POLR2A/RPB1, POLR2B/RPB2 and POLR2F/RPABC2 at the base of the clamp element. The POLR2D/RPB4-POLR2G/RPB7 subcomplex seems to lock the clamp via POLR2G/RPB7 in the closed conformation thus preventing double-stranded DNA to enter the active site cleft. The POLR2D/RPB4-POLR2G/RPB7 subcomplex binds single-stranded DNA and RNA.
• KEGG Pathway:
  R. polymerase (hsa03020)
  Nucleotide excision repair (hsa03420)
  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)
  MicroRNA (miRNA) biogenesis (R-HSA-203927)
  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 II Promoter Escape (R-HSA-73776)
  RNA Polymerase II Transcription Pre-Initiation And Promoter Opening (R-HSA-73779)
  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 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical Intraepithelial neoplasia	DISXP757	Strong	Biomarker	[1]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[2]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of DNA-directed RNA polymerase II subunit RPB4 (POLR2D).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA-directed RNA polymerase II subunit RPB4 (POLR2D).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA-directed RNA polymerase II subunit RPB4 (POLR2D).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA-directed RNA polymerase II subunit RPB4 (POLR2D).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of DNA-directed RNA polymerase II subunit RPB4 (POLR2D).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA-directed RNA polymerase II subunit RPB4 (POLR2D).	[9]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA-directed RNA polymerase II subunit RPB4 (POLR2D).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of DNA-directed RNA polymerase II subunit RPB4 (POLR2D).	[8]

References

• [1] Ascorbic acid ameliorates renal injury in a murine model of contrast-induced nephropathy.BMC Nephrol. 2017 Mar 24;18(1):101. doi: 10.1186/s12882-017-0498-5.
• [2] Evaluation of insulin-like growth factor (IGF-1) and retinol binding protein (RBP-4) levels in patients with newly diagnosed pancreatic adenocarcinoma (PDAC).Pancreatology. 2017 Jul-Aug;17(4):623-628. doi: 10.1016/j.pan.2017.04.001. Epub 2017 Apr 4.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [8] 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.
• [9] 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.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.