Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR081M4)

• DOT Name: Protein Dr1 (DR1)
• Synonyms: Down-regulator of transcription 1; Negative cofactor 2-beta; NC2-beta; TATA-binding protein-associated phosphoprotein
• Gene Name: DR1
• Related Disease:
  Rheumatoid arthritis
  Schizophrenia
  Thyroid gland carcinoma
  Acute myelogenous leukaemia
  Neuroblastoma
  Neoplasm
• UniProt ID: NC2B_HUMAN
• PDB ID: 1JFI
• Pfam ID: PF00808
• Sequence:
  MASSSGNDDDLTIPRAAINKMIKETLPNVRVANDARELVVNCCTEFIHLISSEANEICNK
  SEKKTISPEHVIQALESLGFGSYISEVKEVLQECKTVALKRRKASSRLENLGIPEEELLR
  QQQELFAKARQQQAELAQQEWLQMQQAAQQAQLAAASASASNQAGSSQDEEDDDDI
• 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. Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4.
• Reactome Pathway:
  Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)
  HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[1]
Schizophrenia	DISSRV2N	Strong	Biomarker	[2]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[4]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[5]
Neoplasm	DISZKGEW	Disputed	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein Dr1 (DR1).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein Dr1 (DR1).	[18]

15 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 Protein Dr1 (DR1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein Dr1 (DR1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein Dr1 (DR1).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Protein Dr1 (DR1).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Protein Dr1 (DR1).	[12]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Protein Dr1 (DR1).	[13]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Protein Dr1 (DR1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein Dr1 (DR1).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Protein Dr1 (DR1).	[11]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Protein Dr1 (DR1).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein Dr1 (DR1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein Dr1 (DR1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein Dr1 (DR1).	[19]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Protein Dr1 (DR1).	[20]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Protein Dr1 (DR1).	[21]

References

• [1] Collagen-induced arthritis mediated by HLA-DR1 (*0101) and HLA-DR4 (*0401).Am J Med Sci. 2004 Apr;327(4):169-79. doi: 10.1097/00000441-200404000-00002.
• [2] Schizophrenia and the HLA-DRB1 gene in the Japanese population.Am J Psychiatry. 1999 May;156(5):771-3. doi: 10.1176/ajp.156.5.771.
• [3] Strong association between an HLA-DR antigen and thyroid carcinoma.Tissue Antigens. 1982 Aug;20(2):155-8. doi: 10.1111/j.1399-0039.1982.tb00340.x.
• [4] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [5] Involvement of GTA protein NC2beta in neuroblastoma pathogenesis suggests that it physiologically participates in the regulation of cell proliferation.Mol Cancer. 2008 Jun 6;7:52. doi: 10.1186/1476-4598-7-52.
• [6] Dissecting the non-canonical functions of telomerase.Cytogenet Genome Res. 2008;122(3-4):273-80. doi: 10.1159/000167813. Epub 2009 Jan 30.
• [7] 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.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [13] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [21] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.