Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ0ULJ9)

• DOT Name: DNA-directed RNA polymerase II subunit RPB3 (POLR2C)
• Synonyms: RNA polymerase II subunit 3; RNA polymerase II subunit B3; DNA-directed RNA polymerase II 33 kDa polypeptide; RPB33; DNA-directed RNA polymerase II subunit C; RPB31
• Gene Name: POLR2C
• Related Disease:
  Bone osteosarcoma
  Hepatocellular carcinoma
  Neoplasm
  Osteosarcoma
• UniProt ID: RPB3_HUMAN
• PDB ID: 5IY6; 5IY7; 5IY8; 5IY9; 5IYA; 5IYB; 5IYC; 5IYD; 6DRD; 6O9L; 6XRE; 7LBM
• Pfam ID: PF01000 ; PF01193
• Sequence:
  MPYANQPTVRITELTDENVKFIIENTDLAVANSIRRVFIAEVPIIAIDWVQIDANSSVLH
  DEFIAHRLGLIPLISDDIVDKLQYSRDCTCEEFCPECSVEFTLDVRCNEDQTRHVTSRDL
  ISNSPRVIPVTSRNRDNDPNDYVEQDDILIVKLRKGQELRLRAYAKKGFGKEHAKWNPTA
  GVAFEYDPDNALRHTVYPKPEEWPKSEYSELDEDESQAPYDPNGKPERFYYNVESCGSLR
  PETIVLSALSGLKKKLSDLQTQLSHEIQSDVLTIN
• 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.
• 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[1]

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 RPB3 (POLR2C).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA-directed RNA polymerase II subunit RPB3 (POLR2C).	[4]
Marinol	DM70IK5	Approved	Marinol decreases the expression of DNA-directed RNA polymerase II subunit RPB3 (POLR2C).	[5]
Selenium	DM25CGV	Approved	Selenium increases the expression of DNA-directed RNA polymerase II subunit RPB3 (POLR2C).	[6]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of DNA-directed RNA polymerase II subunit RPB3 (POLR2C).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of DNA-directed RNA polymerase II subunit RPB3 (POLR2C).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA-directed RNA polymerase II subunit RPB3 (POLR2C).	[10]

2 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 increases the methylation of DNA-directed RNA polymerase II subunit RPB3 (POLR2C).	[8]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DNA-directed RNA polymerase II subunit RPB3 (POLR2C).	[9]

References

• [1] SKA1 induces denovo MTX-resistance in osteosarcoma through inhibiting FPGS transcription.FEBS J. 2019 Jun;286(12):2399-2414. doi: 10.1111/febs.14808. Epub 2019 Apr 2.
• [2] Rpb3 promotes hepatocellular carcinoma through its N-terminus.Oncotarget. 2014 Oct 15;5(19):9256-68. doi: 10.18632/oncotarget.2389.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [5] 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.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [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] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.