Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY1Z9C4)

• DOT Name: Transcription initiation factor TFIID subunit 6 (TAF6)
• Synonyms: RNA polymerase II TBP-associated factor subunit E; Transcription initiation factor TFIID 70 kDa subunit; TAF(II)70; TAFII-70; TAFII70; Transcription initiation factor TFIID 80 kDa subunit; TAF(II)80; TAFII-80; TAFII80
• Gene Name: TAF6
• Related Disease:
  Intellectual disability
  Alazami-Yuan syndrome
• UniProt ID: TAF6_HUMAN
• PDB ID: 5FUR; 6F3T; 6MZC; 6MZD; 6MZL; 6MZM; 7EDX; 7EG7; 7EG8; 7EG9; 7EGA; 7EGB; 7EGC; 7EGD; 7EGE; 7EGF; 7EGG; 7EGH; 7EGI; 7EGJ; 7ENA; 7ENC; 8GXQ; 8GXS; 8WAK; 8WAL; 8WAN; 8WAO; 8WAP; 8WAQ; 8WAR; 8WAS
• Pfam ID: PF02969 ; PF07571
• Sequence:
  MAEEKKLKLSNTVLPSESMKVVAESMGIAQIQEETCQLLTDEVSYRIKEIAQDALKFMHM
  GKRQKLTTSDIDYALKLKNVEPLYGFHAQEFIPFRFASGGGRELYFYEEKEVDLSDIINT
  PLPRVPLDVCLKAHWLSIEGCQPAIPENPPPAPKEQQKAEATEPLKSAKPGQEEDGPLKG
  KGQGATTADGKGKEKKAPPLLEGAPLRLKPRSIHELSVEQQLYYKEITEACVGSCEAKRA
  EALQSIATDPGLYQMLPRFSTFISEGVRVNVVQNNLALLIYLMRMVKALMDNPTLYLEKY
  VHELIPAVMTCIVSRQLCLRPDVDNHWALRDFAARLVAQICKHFSTTTNNIQSRITKTFT
  KSWVDEKTPWTTRYGSIAGLAELGHDVIKTLILPRLQQEGERIRSVLDGPVLSNIDRIGA
  DHVQSLLLKHCAPVLAKLRPPPDNQDAYRAEFGSLGPLLCSQVVKARAQAALQAQQVNRT
  TLTITQPRPTLTLSQAPQPGPRTPGLLKVPGSIALPVQTLVSARAAAPPQPSPPPTKFIV
  MSSSSSAPSTQQVLSLSTSAPGSGSTTTSPVTTTVPSVQPIVKLVSTATTAPPSTAPSGP
  GSVQKYIVVSLPPTGEGKGGPTSHPSPVPPPASSPSPLSGSALCGGKQEAGDSPPPAPGT
  PKANGSQPNSGSPQPAP
• Function: The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription. TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13. The TFIID complex structure can be divided into 3 modules TFIID-A, TFIID-B, and TFIID-C. TAF6 homodimer connects TFIID modules, forming a rigid core ; [Isoform 4]: Transcriptional regulator which acts primarily as a positive regulator of transcription. Recruited to the promoters of a number of genes including GADD45A and CDKN1A/p21, leading to transcriptional up-regulation and subsequent induction of apoptosis. Also up-regulates expression of other genes including GCNA/ACRC, HES1 and IFFO1. In contrast, down-regulates transcription of MDM2. Acts as a transcriptional coactivator to enhance transcription of TP53/p53-responsive genes such as DUSP1. Can also activate transcription and apoptosis independently of TP53. Drives apoptosis via the intrinsic apoptotic pathway by up-regulating apoptosis effectors such as BCL2L11/BIM and PMAIP1/NOXA.
• KEGG Pathway: Basal transcription factors (hsa03022)
• 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)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  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
Intellectual disability	DISMBNXP	Strong	Biomarker	[1]
Alazami-Yuan syndrome	DISIYQT5	Limited	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Transcription initiation factor TFIID subunit 6 (TAF6).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transcription initiation factor TFIID subunit 6 (TAF6).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Transcription initiation factor TFIID subunit 6 (TAF6).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Transcription initiation factor TFIID subunit 6 (TAF6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcription initiation factor TFIID subunit 6 (TAF6).	[12]

7 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 Transcription initiation factor TFIID subunit 6 (TAF6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transcription initiation factor TFIID subunit 6 (TAF6).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transcription initiation factor TFIID subunit 6 (TAF6).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcription initiation factor TFIID subunit 6 (TAF6).	[6]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Transcription initiation factor TFIID subunit 6 (TAF6).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Transcription initiation factor TFIID subunit 6 (TAF6).	[9]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Transcription initiation factor TFIID subunit 6 (TAF6).	[13]

References

• [1] Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes. J Clin Invest. 2015 Feb;125(2):636-51. doi: 10.1172/JCI77435. Epub 2015 Jan 9.
• [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] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] 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.
• [8] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [9] 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.
• [10] 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.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.