Details of Drug Off-Target (DOT)

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

• DOT Name: Transcription initiation factor IIE subunit beta (GTF2E2)
• Synonyms: TFIIE-beta; General transcription factor IIE subunit 2
• Gene Name: GTF2E2
• Related Disease:
  Trichothiodystrophy 6, nonphotosensitive
  Trichothiodystrophy
• UniProt ID: T2EB_HUMAN
• PDB ID: 1D8J ; 1D8K ; 5GPY ; 5IY6 ; 5IY7 ; 5IY8 ; 5IY9 ; 5IYA ; 5IYB ; 5IYC ; 5IYD ; 6O9L ; 7EG9 ; 7EGA ; 7EGB ; 7EGC ; 7ENA ; 7ENC ; 7LBM ; 7NVR ; 7NVS ; 7NVT ; 7NVU ; 7NVY ; 7NVZ ; 7NW0 ; 8BVW ; 8BYQ ; 8GXQ ; 8GXS ; 8WAK ; 8WAL ; 8WAN ; 8WAO ; 8WAP ; 8WAQ ; 8WAR ; 8WAS
• Pfam ID: PF18121 ; PF02186
• Sequence:
  MDPSLLRERELFKKRALSTPVVEKRSASSESSSSSSKKKKTKVEHGGSSGSKQNSDHSNG
  SFNLKALSGSSGYKFGVLAKIVNYMKTRHQRGDTHPLTLDEILDETQHLDIGLKQKQWLM
  TEALVNNPKIEVIDGKYAFKPKYNVRDKKALLRLLDQHDQRGLGGILLEDIEEALPNSQK
  AVKALGDQILFVNRPDKKKILFFNDKSCQFSVDEEFQKLWRSVTVDSMDEEKIEEYLKRQ
  GISSMQESGPKKVAPIQRRKKPASQKKRRFKTHNEHLAGVLKDYSDITSSK
• Function: Recruits TFIIH to the initiation complex and stimulates the RNA polymerase II C-terminal domain kinase and DNA-dependent ATPase activities of TFIIH. Both TFIIH and TFIIE are required for promoter clearance by RNA polymerase.
• KEGG Pathway:
  Basal transcription factors (hsa03022)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  RNA Polymerase II HIV Promoter Escape (R-HSA-167162)
  Transcription of the HIV genome (R-HSA-167172)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  RNA polymerase II transcribes snRNA genes (R-HSA-6807505)
  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 Initiation And Promoter Clearance (R-HSA-76042)
  HIV Transcription Initiation (R-HSA-167161)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Trichothiodystrophy 6, nonphotosensitive	DISH6B0O	Strong	Autosomal recessive	[1]
Trichothiodystrophy	DISOMQD2	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[7]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[11]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[12]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID increases the expression of Transcription initiation factor IIE subunit beta (GTF2E2).	[8]

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 increases the methylation of Transcription initiation factor IIE subunit beta (GTF2E2).	[9]

References

• [1] GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy. Am J Hum Genet. 2016 Apr 7;98(4):627-42. doi: 10.1016/j.ajhg.2016.02.008. Epub 2016 Mar 17.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [5] 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.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [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] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [9] 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.
• [10] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] 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.