Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAC9V6L)

• DOT Name: DNA polymerase epsilon subunit 2 (POLE2)
• Synonyms: DNA polymerase II subunit 2; DNA polymerase epsilon subunit B
• Gene Name: POLE2
• Related Disease: Lung adenocarcinoma
• UniProt ID: DPOE2_HUMAN
• PDB ID: 2V6Z; 5VBN; 7PFO; 7PLO
• Pfam ID: PF04042 ; PF12213
• Sequence:
  MAPERLRSRALSAFKLRGLLLRGEAIKYLTEALQSISELELEDKLEKIINAVEKQPLSSN
  MIERSVVEAAVQECSQSVDETIEHVFNIIGAFDIPRFVYNSERKKFLPLLMTNHPAPNLF
  GTPRDKAEMFRERYTILHQRTHRHELFTPPVIGSHPDESGSKFQLKTIETLLGSTTKIGD
  AIVLGMITQLKEGKFFLEDPTGTVQLDLSKAQFHSGLYTEACFVLAEGWFEDQVFHVNAF
  GFPPTEPSSTTRAYYGNINFFGGPSNTSVKTSAKLKQLEEENKDAMFVFLSDVWLDQVEV
  LEKLRIMFAGYSPAPPTCFILCGNFSSAPYGKNQVQALKDSLKTLADIICEYPDIHQSSR
  FVFVPGPEDPGFGSILPRPPLAESITNEFRQRVPFSVFTTNPCRIQYCTQEITVFREDLV
  NKMCRNCVRFPSSNLAIPNHFVKTILSQGHLTPLPLYVCPVYWAYDYALRVYPVPDLLVI
  ADKYDPFTTTNTECLCINPGSFPRSGFSFKVFYPSNKTVEDSKLQGF
• Function: Accessory component of the DNA polymerase epsilon complex. Participates in DNA repair and in chromosomal DNA replication.
• KEGG Pathway:
  D. replication (hsa03030)
  Base excision repair (hsa03410)
  Nucleotide excision repair (hsa03420)
• Reactome Pathway:
  PCNA-Dependent Long Patch Base Excision Repair (R-HSA-5651801)
  Termination of translesion DNA synthesis (R-HSA-5656169)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Gap-filling DNA repair synthesis and ligation in GG-NER (R-HSA-5696397)
  Dual Incision in GG-NER (R-HSA-5696400)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  DNA replication initiation (R-HSA-68952)
  Activation of the pre-replicative complex (R-HSA-68962)
  Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	DNA polymerase epsilon subunit 2 (POLE2) affects the response to substance of Fluorouracil.	[32]
Irinotecan	DMP6SC2	Approved	DNA polymerase epsilon subunit 2 (POLE2) increases the response to substance of Irinotecan.	[33]

34 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 DNA polymerase epsilon subunit 2 (POLE2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[12]
Menadione	DMSJDTY	Approved	Menadione decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[14]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[15]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[16]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[17]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[18]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[20]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[21]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[22]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[23]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[27]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[30]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[7]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of DNA polymerase epsilon subunit 2 (POLE2).	[31]

References

• [1] Knockdown of POLE2 expression suppresses lung adenocarcinoma cell malignant phenotypes invitro.Oncol Rep. 2018 Nov;40(5):2477-2486. doi: 10.3892/or.2018.6659. Epub 2018 Aug 17.
• [2] 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.
• [3] 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.
• [4] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [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] Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [13] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [14] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [15] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [16] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [17] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [18] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [19] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [22] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [23] Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis. Environ Mol Mutagen. 2009 Jan;50(1):46-59.
• [24] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [25] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [26] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [27] 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.
• [28] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [29] 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.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [31] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [32] 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.
• [33] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.