Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCICY31)

• DOT Name: Transcription initiation factor TFIID subunit 4B (TAF4B)
• Synonyms: Transcription initiation factor TFIID 105 kDa subunit; TAF(II)105; TAFII-105; TAFII105
• Gene Name: TAF4B
• Related Disease:
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
  Advanced cancer
  Colon adenocarcinoma
  Spermatogenic failure 13
• UniProt ID: TAF4B_HUMAN
• Pfam ID: PF05236 ; PF07531
• Sequence:
  MPAGLTEPAGAAPPAAVSASGTVTMAPAGALPVRVESTPVALGAVTKAPVSVCVEPTASQ
  PLRSPVGTLVTKVAPVSAPPKVSSGPRLPAPQIVAVKAPNTTTIQFPANLQLPPGTVLIK
  SNSGPLMLVSPQQTVTRAETTSNITSRPAVPANPQTVKICTVPNSSSQLIKKVAVTPVKK
  LAQIGTTVVTTVPKPSSVQSVAVPTSVVTVTPGKPLNTVTTLKPSSLGASSTPSNEPNLK
  AENSAAVQINLSPTMLENVKKCKNFLAMLIKLACSGSQSPEMGQNVKKLVEQLLDAKIEA
  EEFTRKLYVELKSSPQPHLVPFLKKSVVALRQLLPNSQSFIQQCVQQTSSDMVIATCTTT
  VTTSPVVTTTVSSSQSEKSIIVSGATAPRTVSVQTLNPLAGPVGAKAGVVTLHSVGPTAA
  TGGTTAGTGLLQTSKPLVTSVANTVTTVSLQPEKPVVSGTAVTLSLPAVTFGETSGAAIC
  LPSVKPVVSSAGTTSDKPVIGTPVQIKLAQPGPVLSQPAGIPQAVQVKQLVVQQPSGGNE
  KQVTTISHSSTLTIQKCGQKTMPVNTIIPTSQFPPASILKQITLPGNKILSLQASPTQKN
  RIKENVTSCFRDEDDINDVTSMAGVNLNEENACILATNSELVGTLIQSCKDEPFLFIGAL
  QKRILDIGKKHDITELNSDAVNLISQATQERLRGLLEKLTAIAQHRMTTYKASENYILCS
  DTRSQLKFLEKLDQLEKQRKDLEEREMLLKAAKSRSNKEDPEQLRLKQKAKELQQLELAQ
  IQHRDANLTALAAIGPRKKRPLESGIEGLKDNLLASGTSSLTATKQLHRPRITRICLRDL
  IFCMEQEREMKYSRALYLALLK
• Function: Cell type-specific subunit of the general transcription factor TFIID that may function as a gene-selective coactivator in certain cells. TFIID is a multimeric protein complex that plays a central role in mediating promoter responses to various activators and repressors. TAF4B is a transcriptional coactivator of the p65/RELA NF-kappa-B subunit. Involved in the activation of a subset of antiapoptotic genes including TNFAIP3. May be involved in regulating folliculogenesis. Through interaction with OCBA/POU2AF1, acts as a coactivator of B-cell-specific transcription. Plays a role in spermiogenesis and oogenesis.
• Tissue Specificity: Preferentially expressed in ovarian granulosa cells (at protein level). Highly expressed in B-cells.
• KEGG Pathway:
  Basal transcription factors (hsa03022)
  Huntington disease (hsa05016)
• 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 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Supportive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[2]
Colon adenocarcinoma	DISDRE0J	Limited	Biomarker	[2]
Spermatogenic failure 13	DISSC9FY	Limited	Autosomal recessive	[3]

10 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 TFIID subunit 4B (TAF4B).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transcription initiation factor TFIID subunit 4B (TAF4B).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription initiation factor TFIID subunit 4B (TAF4B).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcription initiation factor TFIID subunit 4B (TAF4B).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcription initiation factor TFIID subunit 4B (TAF4B).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription initiation factor TFIID subunit 4B (TAF4B).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Transcription initiation factor TFIID subunit 4B (TAF4B).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Transcription initiation factor TFIID subunit 4B (TAF4B).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcription initiation factor TFIID subunit 4B (TAF4B).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcription initiation factor TFIID subunit 4B (TAF4B).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Transcription initiation factor TFIID subunit 4B (TAF4B).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcription initiation factor TFIID subunit 4B (TAF4B).	[11]

References

• [1] Truncating mutations in TAF4B and ZMYND15 causing recessive azoospermia. J Med Genet. 2014 Apr;51(4):239-44. doi: 10.1136/jmedgenet-2013-102102. Epub 2014 Jan 15.
• [2] TAF4b and Jun/activating protein-1 collaborate to regulate the expression of integrin alpha6 and cancer cell migration properties.Mol Cancer Res. 2010 Apr;8(4):554-68. doi: 10.1158/1541-7786.MCR-09-0159. Epub 2010 Mar 30.
• [3] Maintenance of spermatogenesis requires TAF4b, a gonad-specific subunit of TFIID. Genes Dev. 2005 Apr 1;19(7):794-803. doi: 10.1101/gad.1290105. Epub 2005 Mar 17.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [9] 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.
• [10] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [11] 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.
• [12] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.