Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTOGO05)

• DOT Name: Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1)
• Gene Name: EEPD1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Chromosomal disorder
  Schizophrenia
• UniProt ID: EEPD1_HUMAN
• Pfam ID: PF03372 ; PF12836
• Sequence:
  MGSTLGCHRSIPRDPSDLSHSRKFSAACNFSNILVNQERLNINTATEEELMTLPGVTRAV
  ARSIVEYREYIGGFKKVEDLALVSGVGATKLEQVKFEICVSSKGSSAQHSPSSLRRDLLA
  EQQPHHLATAVPLTPRVNINTATPAQLMSVRGLSEKMALSIVDFRREHGPFRSVEDLVRM
  DGINAAFLDRIRHQVFAERSRPPSTHTNGGLTFTAKPHPSPTSLSLQSEDLDLPPGGPTQ
  IISTRPSVEAFGGTRDGRPVLRLATWNLQGCSVEKANNPGVREVVCMTLLENSIKLLAVQ
  ELLDREALEKFCTELNQPTLPNIRKWKGPRGCWKAVVAEKPSSQLQKGAGYAGFLWDAAA
  GMELRDAGSQESSPSNGHGKLAGPSPYLGRFKVGSHDLTLVNLHLAALTLLGSENPSKNH
  SDGHRLASFAQTLQETLKGEKDVIILGDFGQGPDSNDYDILRKEKFHHLIPAHTFTNIST
  KNPQGSKSLDNIWISKSLKKVFTGHWAVVREGLTNPWIPDNWSWGGVASEHCPVLAEFYT
  EKDWSKKDAPRNGSGVALERSEANIKHER
• Reactome Pathway: NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[12]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[22]

4 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 Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Endonuclease/exonuclease/phosphatase family domain-containing protein 1 (EEPD1).	[20]

References

• [1] The endonuclease EEPD1 mediates synthetic lethality in RAD52-depleted BRCA1 mutant breast cancer cells.Breast Cancer Res. 2017 Nov 16;19(1):122. doi: 10.1186/s13058-017-0912-8.
• [2] EEPD1 Rescues Stressed Replication Forks and Maintains Genome Stability by Promoting End Resection and Homologous Recombination Repair.PLoS Genet. 2015 Dec 18;11(12):e1005675. doi: 10.1371/journal.pgen.1005675. eCollection 2015 Dec.
• [3] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [9] 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.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [20] 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.
• [21] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.