Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDYS5G4)

• DOT Name: Transcription initiation factor TFIID subunit 1 (TAF1)
• Synonyms: EC 2.3.1.48; EC 2.7.11.1; Cell cycle gene 1 protein; TBP-associated factor 250 kDa; p250; Transcription initiation factor TFIID 250 kDa subunit; TAF(II)250; TAFII-250; TAFII250
• Gene Name: TAF1
• Related Disease:
  Intellectual disability, X-linked, syndromic 33
  Abdominal aortic aneurysm
  Acute myelogenous leukaemia
  Advanced cancer
  Cerebral degeneration
  Colorectal carcinoma
  Movement disorder
  Parkinsonism-dystonia, infantile
  Paroxysmal dyskinesia
  Prostate cancer
  T-cell acute lymphoblastic leukaemia
  Tardive dyskinesia
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland follicular carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Thyroid tumor
  X-linked dystonia-parkinsonism
  X-linked intellectual disability-global development delay-facial dysmorphism-sacral caudal remnant syndrome
  Bjornstad syndrome
  Chronic obstructive pulmonary disease
  Colon adenocarcinoma
  Hepatocellular carcinoma
  Intellectual disability
  Neoplasm
  Neuroblastoma
  Neurodevelopmental disorder
  Non-insulin dependent diabetes
  Parkinsonian disorder
• UniProt ID: TAF1_HUMAN
• PDB ID: 1EQF ; 3AAD ; 3UV4 ; 3UV5 ; 4RGW ; 4YYM ; 4YYN ; 5FUR ; 5I1Q ; 5I29 ; 5MG2 ; 6BQD ; 6FIC ; 6MZD ; 6MZL ; 6MZM ; 6P38 ; 6P39 ; 6P3A ; 7EDX ; 7EG7 ; 7EG8 ; 7EG9 ; 7EGA ; 7EGB ; 7EGC ; 7EGD ; 7EGE ; 7EGH ; 7EGI ; 7EGJ ; 7ENA ; 7ENC ; 7JJG ; 7JJH ; 7JSP ; 7JTC ; 7K03 ; 7K0D ; 7K0U ; 7K1P ; 7K27 ; 7K3O ; 7K42 ; 7K6F ; 7L6X ; 7LB0 ; 7LB1 ; 7LB2 ; 7LB3 ; 7N42 ; 7P4S ; 7T2I ; 7T36 ; 8GXQ ; 8GXS ; 8WAK ; 8WAL ; 8WAN ; 8WAO ; 8WAP ; 8WAQ ; 8WAR ; 8WAS
• EC Number: 2.3.1.48; 2.7.11.1
• Pfam ID: PF00439 ; PF12157 ; PF09247 ; PF15288
• Sequence:
  MGPGCDLLLRTAATITAAAIMSDTDSDEDSAGGGPFSLAGFLFGNINGAGQLEGESVLDD
  ECKKHLAGLGALGLGSLITELTANEELTGTDGALVNDEGWVRSTEDAVDYSDINEVAEDE
  SRRYQQTMGSLQPLCHSDYDEDDYDADCEDIDCKLMPPPPPPPGPMKKDKDQDSITGVSE
  NGEGIILPSIIAPSSLASEKVDFSSSSDSESEMGPQEATQAESEDGKLTLPLAGIMQHDA
  TKLLPSVTELFPEFRPGKVLRFLRLFGPGKNVPSVWRSARRKRKKKHRELIQEEQIQEVE
  CSVESEVSQKSLWNYDYAPPPPPEQCLSDDEITMMAPVESKFSQSTGDIDKVTDTKPRVA
  EWRYGPARLWYDMLGVPEDGSGFDYGFKLRKTEHEPVIKSRMIEEFRKLEENNGTDLLAD
  ENFLMVTQLHWEDDIIWDGEDVKHKGTKPQRASLAGWLPSSMTRNAMAYNVQQGFAATLD
  DDKPWYSIFPIDNEDLVYGRWEDNIIWDAQAMPRLLEPPVLTLDPNDENLILEIPDEKEE
  ATSNSPSKESKKESSLKKSRILLGKTGVIKEEPQQNMSQPEVKDPWNLSNDEYYYPKQQG
  LRGTFGGNIIQHSIPAVELRQPFFPTHMGPIKLRQFHRPPLKKYSFGALSQPGPHSVQPL
  LKHIKKKAKMREQERQASGGGEMFFMRTPQDLTGKDGDLILAEYSEENGPLMMQVGMATK
  IKNYYKRKPGKDPGAPDCKYGETVYCHTSPFLGSLHPGQLLQAFENNLFRAPIYLHKMPE
  TDFLIIRTRQGYYIRELVDIFVVGQQCPLFEVPGPNSKRANTHIRDFLQVFIYRLFWKSK
  DRPRRIRMEDIKKAFPSHSESSIRKRLKLCADFKRTGMDSNWWVLKSDFRLPTEEEIRAM
  VSPEQCCAYYSMIAAEQRLKDAGYGEKSFFAPEEENEEDFQMKIDDEVRTAPWNTTRAFI
  AAMKGKCLLEVTGVADPTGCGEGFSYVKIPNKPTQQKDDKEPQPVKKTVTGTDADLRRLS
  LKNAKQLLRKFGVPEEEIKKLSRWEVIDVVRTMSTEQARSGEGPMSKFARGSRFSVAEHQ
  ERYKEECQRIFDLQNKVLSSTEVLSTDTDSSSAEDSDFEEMGKNIENMLQNKKTSSQLSR
  EREEQERKELQRMLLAAGSAASGNNHRDDDTASVTSLNSSATGRCLKIYRTFRDEEGKEY
  VRCETVRKPAVIDAYVRIRTTKDEEFIRKFALFDEQHREEMRKERRRIQEQLRRLKRNQE
  KEKLKGPPEKKPKKMKERPDLKLKCGACGAIGHMRTNKFCPLYYQTNAPPSNPVAMTEEQ
  EEELEKTVIHNDNEELIKVEGTKIVLGKQLIESADEVRRKSLVLKFPKQQLPPKKKRRVG
  TTVHCDYLNRPHKSIHRRRTDPMVTLSSILESIINDMRDLPNTYPFHTPVNAKVVKDYYK
  IITRPMDLQTLRENVRKRLYPSREEFREHLELIVKNSATYNGPKHSLTQISQSMLDLCDE
  KLKEKEDKLARLEKAINPLLDDDDQVAFSFILDNIVTQKMMAVPDSWPFHHPVNKKFVPD
  YYKVIVNPMDLETIRKNISKHKYQSRESFLDDVNLILANSVKYNGPESQYTKTAQEIVNV
  CYQTLTEYDEHLTQLEKDICTAKEAALEEAELESLDPMTPGPYTPQPPDLYDTNTSLSMS
  RDASVFQDESNMSVLDIPSATPEKQVTQEGEDGDGDLADEEEGTVQQPQASVLYEDLLMS
  EGEDDEEDAGSDEEGDNPFSAIQLSESGSDSDVGSGGIRPKQPRMLQENTRMDMENEESM
  MSYEGDGGEASHGLEDSNISYGSYEEPDPKSNTQDTSFSSIGGYEVSEEEEDEEEEEQRS
  GPSVLSQVHLSEDEEDSEDFHSIAGDSDLDSDE
• 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. TAF1 is the largest component and core scaffold of the TFIID complex, involved in nucleating complex assembly. TAF1 forms a promoter DNA binding subcomplex of TFIID, together with TAF7 and TAF2. Contains novel N- and C-terminal Ser/Thr kinase domains which can autophosphorylate or transphosphorylate other transcription factors. Phosphorylates TP53 on 'Thr-55' which leads to MDM2-mediated degradation of TP53. Phosphorylates GTF2A1 and GTF2F1 on Ser residues. Possesses DNA-binding activity. Essential for progression of the G1 phase of the cell cycle. Exhibits histone acetyltransferase activity towards histones H3 and H4.
• 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 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

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, X-linked, syndromic 33	DIS945F9	Definitive	X-linked	[1]
Abdominal aortic aneurysm	DISD06OF	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Cerebral degeneration	DISUMR0A	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[6]
Parkinsonism-dystonia, infantile	DISUX01X	Strong	Genetic Variation	[7]
Paroxysmal dyskinesia	DIS5XVXE	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Altered Expression	[8]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Genetic Variation	[9]
Tardive dyskinesia	DISKA5RC	Strong	Genetic Variation	[10]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[11]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[11]
Thyroid gland follicular carcinoma	DISFK2QT	Strong	Biomarker	[12]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Biomarker	[13]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[11]
X-linked dystonia-parkinsonism	DIS5TT9O	Moderate	X-linked	[14]
X-linked intellectual disability-global development delay-facial dysmorphism-sacral caudal remnant syndrome	DISGQNCA	Supportive	X-linked	[1]
Bjornstad syndrome	DISO267N	Limited	Genetic Variation	[15]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Altered Expression	[16]
Colon adenocarcinoma	DISDRE0J	Limited	Biomarker	[17]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[18]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[19]
Neoplasm	DISZKGEW	Limited	Biomarker	[17]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[20]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[21]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[22]
Parkinsonian disorder	DISHGY45	Limited	Biomarker	[23]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Transcription initiation factor TFIID subunit 1 (TAF1) affects the response to substance of Paclitaxel.	[31]

5 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 1 (TAF1).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transcription initiation factor TFIID subunit 1 (TAF1).	[26]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Transcription initiation factor TFIID subunit 1 (TAF1).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Transcription initiation factor TFIID subunit 1 (TAF1).	[28]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Transcription initiation factor TFIID subunit 1 (TAF1).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the methylation of Transcription initiation factor TFIID subunit 1 (TAF1).	[25]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Transcription initiation factor TFIID subunit 1 (TAF1).	[29]

References

• [1] TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations. Am J Hum Genet. 2015 Dec 3;97(6):922-32. doi: 10.1016/j.ajhg.2015.11.005.
• [2] Neutrophil Elastase-Derived Fibrin Degradation Products Indicate Presence of Abdominal Aortic Aneurysms and Correlate with Intraluminal Thrombus Volume.Thromb Haemost. 2018 Feb;118(2):329-339. doi: 10.1160/TH17-05-0348. Epub 2018 Jan 29.
• [3] TAF1 plays a critical role in AML1-ETO driven leukemogenesis.Nat Commun. 2019 Oct 29;10(1):4925. doi: 10.1038/s41467-019-12735-z.
• [4] Frameshift Mutations in the Mononucleotide Repeats of TAF1 and TAF1L Genes in Gastric and Colorectal Cancers with Regional Heterogeneity.Pathol Oncol Res. 2017 Jan;23(1):125-130. doi: 10.1007/s12253-016-0107-0. Epub 2016 Aug 29.
• [5] Genetics and pharmacological treatment of dystonia.Int Rev Neurobiol. 2011;98:525-49. doi: 10.1016/B978-0-12-381328-2.00019-5.
• [6] A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism.Ann Neurol. 2019 Jun;85(6):812-822. doi: 10.1002/ana.25488. Epub 2019 May 3.
• [7] Isolated and combined dystonia syndromes - an update on new genes and their phenotypes.Eur J Neurol. 2015 Apr;22(4):610-7. doi: 10.1111/ene.12650. Epub 2015 Jan 29.
• [8] TAF1 differentially enhances androgen receptor transcriptional activity via its N-terminal kinase and ubiquitin-activating and -conjugating domains.Mol Endocrinol. 2010 Apr;24(4):696-708. doi: 10.1210/me.2009-0229. Epub 2010 Feb 24.
• [9] SET-NUP214 is a recurrent lineage-specific fusion transcript associated with corticosteroid/chemotherapy resistance in adult T-ALL.Blood. 2014 Mar 20;123(12):1860-3. doi: 10.1182/blood-2013-08-521518. Epub 2014 Jan 21.
• [10] Neuropsychological and psychiatric outcome of GPi-deep brain stimulation in dystonia.Brain Stimul. 2017 Sep-Oct;10(5):994-996. doi: 10.1016/j.brs.2017.06.002. Epub 2017 Jun 9.
• [11] Targeting the proteasome as a promising therapeutic strategy in thyroid cancer.J Surg Oncol. 2012 Mar 15;105(4):357-64. doi: 10.1002/jso.22113. Epub 2011 Oct 17.
• [12] Low concentrations of the histone deacetylase inhibitor, depsipeptide (FR901228), increase expression of the Na(+)/I(-) symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells.J Clin Endocrinol Metab. 2001 Jul;86(7):3430-5. doi: 10.1210/jcem.86.7.7621.
• [13] Synergy of a herpes oncolytic virus and paclitaxel for anaplastic thyroid cancer.Clin Cancer Res. 2008 Mar 1;14(5):1519-28. doi: 10.1158/1078-0432.CCR-07-4628.
• [14] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [15] Genetics of dystonia.Semin Neurol. 2011 Nov;31(5):441-8. doi: 10.1055/s-0031-1299783. Epub 2012 Jan 21.
• [16] Impaired Skeletal Muscle Kynurenine Metabolism in Patients with Chronic Obstructive Pulmonary Disease.J Clin Med. 2019 Jun 26;8(7):915. doi: 10.3390/jcm8070915.
• [17] Inhibition of integrin (V)(6) changes fibril thickness of stromal collagen in experimental carcinomas.Cell Commun Signal. 2018 Jul 2;16(1):36. doi: 10.1186/s12964-018-0249-7.
• [18] Identification of potential transcription factors, long noncoding RNAs, and microRNAs associated with hepatocellular carcinoma.J Cancer Res Ther. 2018 Sep;14(Supplement):S622-S627. doi: 10.4103/0973-1482.204846.
• [19] Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.Hum Mutat. 2019 Oct 23:10.1002/humu.23936. doi: 10.1002/humu.23936. Online ahead of print.
• [20] NHLH2: at the intersection of obesity and fertility.Trends Endocrinol Metab. 2013 Aug;24(8):385-90. doi: 10.1016/j.tem.2013.04.003. Epub 2013 May 17.
• [21] TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish.Sci Rep. 2019 Jul 24;9(1):10730. doi: 10.1038/s41598-019-46632-8.
• [22] Comparison of Transcriptome Between Type 2 Diabetes Mellitus and Impaired Fasting Glucose.Med Sci Monit. 2016 Dec 1;22:4699-4706. doi: 10.12659/msm.896772.
• [23] Long-term outcomes of pallidal deep brain stimulation in X-linked dystonia parkinsonism (XDP): Up to 84 months follow-up and review of literature.Parkinsonism Relat Disord. 2019 Mar;60:81-86. doi: 10.1016/j.parkreldis.2018.09.022. Epub 2018 Sep 21.
• [24] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [25] Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic. Oncotarget. 2015 Aug 28;6(25):21493-506. doi: 10.18632/oncotarget.4085.
• [26] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [27] Peroxisome proliferator-activated receptor gamma-independent suppression of androgen receptor expression by troglitazone mechanism and pharmacologic exploitation. Cancer Res. 2007 Apr 1;67(7):3229-38. doi: 10.1158/0008-5472.CAN-06-2759.
• [28] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [29] 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.
• [30] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.
• [31] MIAT shuttled by tumor-secreted exosomes promotes paclitaxel resistance in esophageal cancer cells by activating the TAF1/SREBF1 axis. J Biochem Mol Toxicol. 2023 Aug;37(8):e23380. doi: 10.1002/jbt.23380. Epub 2023 May 3.