Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRWLF6D)

• DOT Name: Dr1-associated corepressor (DRAP1)
• Synonyms: Dr1-associated protein 1; Negative cofactor 2-alpha; NC2-alpha
• Gene Name: DRAP1
• Related Disease:
  Angiosarcoma
  Melanoma
• UniProt ID: NC2A_HUMAN
• PDB ID: 1JFI
• Pfam ID: PF00808
• Sequence:
  MPSKKKKYNARFPPARIKKIMQTDEEIGKVAAAVPVIISRALELFLESLLKKACQVTQSR
  NAKTMTTSHLKQCIELEQQFDFLKDLVASVPDMQGDGEDNHMDGDKGARRGRKPGSGGRK
  NGGMGTKSKDKKLSGTDSEQEDESEDTDTDGEEETSQPPPQASHPSAHFQSPPTPFLPFA
  STLPLPPAPPGPSAPDEEDEEDYDS
• Function: The association of the DR1/DRAP1 heterodimer with TBP results in a functional repression of both activated and basal transcription of class II genes. This interaction precludes the formation of a transcription-competent complex by inhibiting the association of TFIIA and/or TFIIB with TBP. Can bind to DNA on its own.
• Tissue Specificity: Ubiquitous. Highly expressed in adult testis, heart, skeletal muscle, pancreas and brain, and in fetal brain, liver and kidney.
• Reactome Pathway:
  Signaling by Activin (R-HSA-1502540)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Angiosarcoma	DISIYS9W	Strong	Biomarker	[1]
Melanoma	DIS1RRCY	Strong	Biomarker	[2]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Dr1-associated corepressor (DRAP1) affects the response to substance of Cisplatin.	[14]
Methotrexate	DM2TEOL	Approved	Dr1-associated corepressor (DRAP1) affects the response to substance of Methotrexate.	[14]
Mitomycin	DMH0ZJE	Approved	Dr1-associated corepressor (DRAP1) affects the response to substance of Mitomycin.	[14]
Topotecan	DMP6G8T	Approved	Dr1-associated corepressor (DRAP1) affects the response to substance of Topotecan.	[14]

1 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 Dr1-associated corepressor (DRAP1).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dr1-associated corepressor (DRAP1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dr1-associated corepressor (DRAP1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dr1-associated corepressor (DRAP1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Dr1-associated corepressor (DRAP1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dr1-associated corepressor (DRAP1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Dr1-associated corepressor (DRAP1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Dr1-associated corepressor (DRAP1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dr1-associated corepressor (DRAP1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dr1-associated corepressor (DRAP1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dr1-associated corepressor (DRAP1).	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Dr1-associated corepressor (DRAP1).	[13]

References

• [1] Identification of potential target genes associated with the effect of propranolol on angiosarcoma via microarray analysis.Oncol Lett. 2017 Jun;13(6):4267-4275. doi: 10.3892/ol.2017.5968. Epub 2017 Mar 31.
• [2] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [13] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [14] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.