Details of Drug Off-Target (DOT)

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

• DOT Name: Transcription initiation factor TFIID subunit 8 (TAF8)
• Synonyms: Protein taube nuss; TBP-associated factor 43 kDa; TBP-associated factor 8; Transcription initiation factor TFIID 43 kDa subunit; TAFII-43; TAFII43; hTAFII43
• Gene Name: TAF8
• Related Disease:
  Intellectual disability
  Acute leukaemia
  Breast cancer
  Hepatitis C virus infection
  HIV infectious disease
  Lung adenocarcinoma
  Neoplasm
  Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy
  T-cell leukaemia
  Brain infarction
  Glaucoma/ocular hypertension
• UniProt ID: TAF8_HUMAN
• PDB ID: 4WV4; 4WV6; 5FUR; 6MZC; 6MZL; 6MZM; 7EDX; 7EG7; 7EG8; 7EG9; 7EGA; 7EGB; 7EGC; 7EGD; 7EGE; 7EGG; 7EGH; 7EGI; 7EGJ; 7ENA; 7ENC; 8GXQ; 8GXS; 8WAK; 8WAL; 8WAN; 8WAO; 8WAP; 8WAQ; 8WAR; 8WAS
• Pfam ID: PF07524 ; PF10406
• Sequence:
  MADAAATAGAGGSGTRSGSKQSTNPADNYHLARRRTLQVVVSSLLTEAGFESAEKASVET
  LTEMLQSYISEIGRSAKSYCEHTARTQPTLSDIVVTLVEMGFNVDTLPAYAKRSQRMVIT
  APPVTNQPVTPKALTAGQNRPHPPHIPSHFPEFPDPHTYIKTPTYREPVSDYQVLREKAA
  SQRRDVERALTRFMAKTGETQSLFKDDVSTFPLIAARPFTIPYLTALLPSELEMQQMEET
  DSSEQDEQTDTENLALHISMEDSGAEKENTSVLQQNPSLSGSRNGEENIIDNPYLRPVKK
  PKIRRKKSLS
• 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. TAF8 is involved in forming the TFIID-B module, together with TAF5. Mediates both basal and activator-dependent transcription. Plays a role in the differentiation of preadipocyte fibroblasts to adipocytes, however, does not seem to play a role in differentiation of myoblasts. Required for the integration of TAF10 in the TAF complex. May be important for survival of cells of the inner cell mass which constitute the pluripotent cell population of the early embryo.
• KEGG Pathway: Basal transcription factors (hsa03022)
• Reactome Pathway: RNA polymerase II transcribes snRNA genes (R-HSA-6807505)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[4]
HIV infectious disease	DISO97HC	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy	DISEVP9C	Strong	Autosomal recessive	[7]
T-cell leukaemia	DISJ6YIF	Strong	Altered Expression	[8]
Brain infarction	DISPPGYK	Limited	Biomarker	[9]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transcription initiation factor TFIID subunit 8 (TAF8).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transcription initiation factor TFIID subunit 8 (TAF8).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcription initiation factor TFIID subunit 8 (TAF8).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transcription initiation factor TFIID subunit 8 (TAF8).	[14]

References

• [1] Homozygous TAF8 mutation in a patient with intellectual disability results in undetectable TAF8 protein, but preserved RNA polymerase II transcription.Hum Mol Genet. 2018 Jun 15;27(12):2171-2186. doi: 10.1093/hmg/ddy126.
• [2] TAF-I deficiency inhibits proliferation and promotes apoptosis by rescuing PP2A and inhibiting the AKT/GSK-3 pathway in leukemic cells.Exp Ther Med. 2019 Nov;18(5):3801-3808. doi: 10.3892/etm.2019.8012. Epub 2019 Sep 17.
• [3] Discovery of over-expressed genes and genetic alterations in breast cancer cells using a combination of suppression subtractive hybridization, multiplex FISH and comparative genomic hybridization.Int J Oncol. 2002 Sep;21(3):499-507.
• [4] Evaluation of Safety and Effectiveness of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Switch Followed by Ledipasvir/Sofosbuvir HCV Therapy in HIV-HCV Coinfection.Open Forum Infect Dis. 2019 Jul 1;6(7):ofz318. doi: 10.1093/ofid/ofz318.
• [5] Darunavir for the treatment of HIV infection.Expert Opin Pharmacother. 2018 Jul;19(10):1149-1163. doi: 10.1080/14656566.2018.1484901. Epub 2018 Jun 18.
• [6] miR-21-5p promotes lung adenocarcinoma progression partially through targeting SET/TAF-I.Life Sci. 2019 Aug 15;231:116539. doi: 10.1016/j.lfs.2019.06.014. Epub 2019 Jun 6.
• [7] [National Organization of Norwegian Student Nurses]. Sykepleien. 1977 Sep 20;64(15):843.
• [8] The human interleukin-2 receptor: normal and abnormal expression in T cells and in leukemias induced by the human T-lymphotropic retroviruses.Ann Intern Med. 1986 Oct;105(4):560-72. doi: 10.7326/0003-4819-105-4-560.
• [9] Neuroprotective Effect and Mechanism of Action of Tetramethylpyrazine Nitrone for Ischemic Stroke Therapy.Neuromolecular Med. 2018 Mar;20(1):97-111. doi: 10.1007/s12017-018-8478-x. Epub 2018 Feb 6.
• [10] Tetramethylpyrazine nitrone protects retinal ganglion cells against N-methyl-d-aspartate-induced excitotoxicity.J Neurochem. 2017 May;141(3):373-386. doi: 10.1111/jnc.13970. Epub 2017 Mar 3.
• [11] 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.
• [12] 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.
• [13] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.