Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNE038N)

• DOT Name: TATA-binding protein-associated factor 2N (TAF15)
• Synonyms: 68 kDa TATA-binding protein-associated factor; TAF(II)68; TAFII68; RNA-binding protein 56
• Gene Name: TAF15
• Related Disease:
  Leukemia
  Acute lymphocytic leukaemia
  Advanced cancer
  Amyotrophic lateral sclerosis type 1
  Bipolar disorder
  Chondrosarcoma
  Chromosomal disorder
  Ewing sarcoma
  Familial amyotrophic lateral sclerosis
  Frontotemporal dementia
  Gastric cancer
  Gastric neoplasm
  GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
  Hereditary diffuse gastric adenocarcinoma
  Liposarcoma
  Mixed phenotype acute leukemia
  Neoplasm
  Schizophrenia
  Osteosarcoma
  Pick disease
  Acute leukaemia
  Acute myelogenous leukaemia
  Amyotrophic lateral sclerosis
  Cutaneous squamous cell carcinoma
  leukaemia
  Nervous system disease
• UniProt ID: RBP56_HUMAN
• PDB ID: 2MMY; 8ONS
• Pfam ID: PF00076
• Sequence:
  MSDSGSYGQSGGEQQSYSTYGNPGSQGYGQASQSYSGYGQTTDSSYGQNYSGYSSYGQSQ
  SGYSQSYGGYENQKQSSYSQQPYNNQGQQQNMESSGSQGGRAPSYDQPDYGQQDSYDQQS
  GYDQHQGSYDEQSNYDQQHDSYSQNQQSYHSQRENYSHHTQDDRRDVSRYGEDNRGYGGS
  QGGGRGRGGYDKDGRGPMTGSSGGDRGGFKNFGGHRDYGPRTDADSESDNSDNNTIFVQG
  LGEGVSTDQVGEFFKQIGIIKTNKKTGKPMINLYTDKDTGKPKGEATVSFDDPPSAKAAI
  DWFDGKEFHGNIIKVSFATRRPEFMRGGGSGGGRRGRGGYRGRGGFQGRGGDPKSGDWVC
  PNPSCGNMNFARRNSCNQCNEPRPEDSRPSGGDFRGRGYGGERGYRGRGGRGGDRGGYGG
  DRSGGGYGGDRSSGGGYSGDRSGGGYGGDRSGGGYGGDRGGGYGGDRGGGYGGDRGGGYG
  GDRGGYGGDRGGGYGGDRGGYGGDRGGYGGDRGGYGGDRGGYGGDRSRGGYGGDRGGGSG
  YGGDRSGGYGGDRSGGGYGGDRGGGYGGDRGGYGGKMGGRNDYRNDQRNRPY
• Function: RNA and ssDNA-binding protein that may play specific roles during transcription initiation at distinct promoters. Can enter the preinitiation complex together with the RNA polymerase II (Pol II).
• Tissue Specificity: Ubiquitous. Observed in all fetal and adult tissues.
• KEGG Pathway:
  Basal transcription factors (hsa03022)
  Transcriptio.l misregulation in cancer (hsa05202)
• 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

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukemia	DISNAKFL	Definitive	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Genetic Variation	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Chondrosarcoma	DIS4I7JB	Strong	Biomarker	[6]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[1]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[7]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Genetic Variation	[8]
Frontotemporal dementia	DISKYHXL	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[10]
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	DIS6Z6TF	Strong	Biomarker	[11]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[10]
Liposarcoma	DIS8IZVM	Strong	Altered Expression	[8]
Mixed phenotype acute leukemia	DISNCHV9	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[13]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[14]
Pick disease	DISP6X50	moderate	Biomarker	[9]
Acute leukaemia	DISDQFDI	Limited	Altered Expression	[15]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[15]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Autosomal dominant	[16]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Altered Expression	[17]
leukaemia	DISS7D1V	Limited	Biomarker	[1]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of TATA-binding protein-associated factor 2N (TAF15).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of TATA-binding protein-associated factor 2N (TAF15).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of TATA-binding protein-associated factor 2N (TAF15).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of TATA-binding protein-associated factor 2N (TAF15).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of TATA-binding protein-associated factor 2N (TAF15).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TATA-binding protein-associated factor 2N (TAF15).	[24]
Marinol	DM70IK5	Approved	Marinol increases the expression of TATA-binding protein-associated factor 2N (TAF15).	[26]
Menadione	DMSJDTY	Approved	Menadione affects the expression of TATA-binding protein-associated factor 2N (TAF15).	[27]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of TATA-binding protein-associated factor 2N (TAF15).	[28]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of TATA-binding protein-associated factor 2N (TAF15).	[29]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of TATA-binding protein-associated factor 2N (TAF15).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of TATA-binding protein-associated factor 2N (TAF15).	[31]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of TATA-binding protein-associated factor 2N (TAF15).	[34]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of TATA-binding protein-associated factor 2N (TAF15).	[35]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of TATA-binding protein-associated factor 2N (TAF15).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of TATA-binding protein-associated factor 2N (TAF15).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of TATA-binding protein-associated factor 2N (TAF15).	[30]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of TATA-binding protein-associated factor 2N (TAF15).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of TATA-binding protein-associated factor 2N (TAF15).	[33]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of TATA-binding protein-associated factor 2N (TAF15).	[32]

References

• [1] Mixed Phenotype Acute Leukemia with t(12;17)(p13;q21)/TAF15-ZNF384 and Other Chromosome Abnormalities.Cytogenet Genome Res. 2016;149(3):165-170. doi: 10.1159/000448447. Epub 2016 Sep 9.
• [2] Identification of the TAF15-ZNF384 fusion gene in two new cases of acute lymphoblastic leukemia with a t(12;17)(p13;q12).Cancer Genet. 2011 Mar;204(3):147-52. doi: 10.1016/j.cancergen.2011.01.003.
• [3] The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-kappaB target genes by interaction with NFKBIZ.Oncogene. 2009 Jan 15;28(2):270-8. doi: 10.1038/onc.2008.378. Epub 2008 Oct 13.
• [4] Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis.Am J Med Genet B Neuropsychiatr Genet. 2011 Apr;156B(3):285-90. doi: 10.1002/ajmg.b.31158. Epub 2011 Jan 13.
• [5] Integrated transcriptome and methylome analysis in youth at high risk for bipolar disorder: a preliminary analysis.Transl Psychiatry. 2017 Mar 14;7(3):e1059. doi: 10.1038/tp.2017.32.
• [6] NR4A3 fusion proteins trigger an axon guidance switch that marks the difference between EWSR1 and TAF15 translocated extraskeletal myxoid chondrosarcomas.J Pathol. 2019 Sep;249(1):90-101. doi: 10.1002/path.5284. Epub 2019 May 14.
• [7] An autopsy case of frontotemporal lobar degeneration with the appearance of fused in sarcoma inclusions (basophilic inclusion body disease) clinically presenting corticobasal syndrome.Neuropathology. 2016 Feb;36(1):77-87. doi: 10.1111/neup.12232. Epub 2015 Jul 31.
• [8] mRNA and protein levels of FUS, EWSR1, and TAF15 are upregulated in liposarcoma.Genes Chromosomes Cancer. 2011 May;50(5):338-47. doi: 10.1002/gcc.20858. Epub 2011 Feb 22.
• [9] Xrp1 genetically interacts with the ALS-associated FUS orthologue caz and mediates its toxicity.J Cell Biol. 2018 Nov 5;217(11):3947-3964. doi: 10.1083/jcb.201802151. Epub 2018 Sep 12.
• [10] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [11] The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease.Brain Res. 2012 Jun 26;1462:61-80. doi: 10.1016/j.brainres.2012.01.016. Epub 2012 Jan 21.
• [12] Extraskeletal myxoid chondrosarcoma with non-EWSR1-NR4A3 variant fusions correlate with rhabdoid phenotype and high-grade morphology.Hum Pathol. 2014 May;45(5):1084-91. doi: 10.1016/j.humpath.2014.01.007. Epub 2014 Jan 28.
• [13] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [14] Prediction of response to neoadjuvant chemotherapy for osteosarcoma by gene-expression profiles.Int J Oncol. 2004 Mar;24(3):647-55.
• [15] Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia.Cancer Res. 2002 Oct 1;62(19):5408-12.
• [16] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [17] USF1-induced upregulation of LINC01048 promotes cell proliferation and apoptosis in cutaneous squamous cell carcinoma by binding to TAF15 to transcriptionally activate YAP1.Cell Death Dis. 2019 Apr 1;10(4):296. doi: 10.1038/s41419-019-1516-2.
• [18] Role of FET proteins in neurodegenerative disorders.RNA Biol. 2016 Nov;13(11):1089-1102. doi: 10.1080/15476286.2016.1211225. Epub 2016 Jul 14.
• [19] 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.
• [20] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [21] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [22] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells. Anticancer Res. 2015 Nov;35(11):5827-37.
• [27] 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.
• [28] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [30] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [31] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [32] 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.
• [33] 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.
• [34] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [35] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [36] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.