Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOELRF6)

• DOT Name: DNA polymerase epsilon subunit 3 (POLE3)
• Synonyms: Arsenic-transactivated protein; AsTP; Chromatin accessibility complex 17 kDa protein; CHRAC-17; HuCHRAC17; DNA polymerase II subunit 3; DNA polymerase epsilon subunit p17
• Gene Name: POLE3
• Related Disease:
  Adult lymphoma
  Advanced cancer
  Alzheimer disease
  Dementia
  Gastric cancer
  Hepatitis C virus infection
  HIV infectious disease
  Lymphoma
  Neoplasm
  Non-hodgkin lymphoma
  Obesity
  Pediatric lymphoma
  Pulmonary fibrosis
  Retinopathy
  Factor IX deficiency
  Epstein barr virus infection
• UniProt ID: DPOE3_HUMAN
• Pfam ID: PF00808
• Sequence:
  MAERPEDLNLPNAVITRIIKEALPDGVNISKEARSAISRAASVFVLYATSCANNFAMKGK
  RKTLNASDVLSAMEEMEFQRFVTPLKEALEAYRREQKGKKEASEQKKKDKDKKTDSEEQD
  KSRDEDNDEDEERLEEEEQNEEEEVDN
• Function: Accessory component of the DNA polymerase epsilon complex. Participates in DNA repair and in chromosomal DNA replication. Forms a complex with CHRAC1 and binds naked DNA, which is then incorporated into chromatin, aided by the nucleosome-remodeling activity of ISWI/SNF2H and ACF1. Does not enhance nucleosome sliding activity of the ACF-5 ISWI chromatin remodeling complex.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway:
  D. replication (hsa03030)
  ATP-dependent chromatin remodeling (hsa03082)
  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

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Dementia	DISXL1WY	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
HIV infectious disease	DISO97HC	Strong	Biomarker	[7]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[8]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[9]
Obesity	DIS47Y1K	Strong	Genetic Variation	[10]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[1]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[11]
Retinopathy	DISB4B0F	Strong	Biomarker	[12]
Factor IX deficiency	DISHN9SC	moderate	Biomarker	[13]
Epstein barr virus infection	DISOO0WT	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of DNA polymerase epsilon subunit 3 (POLE3).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA polymerase epsilon subunit 3 (POLE3).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA polymerase epsilon subunit 3 (POLE3).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA polymerase epsilon subunit 3 (POLE3).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA polymerase epsilon subunit 3 (POLE3).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA polymerase epsilon subunit 3 (POLE3).	[20]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA polymerase epsilon subunit 3 (POLE3).	[21]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DNA polymerase epsilon subunit 3 (POLE3).	[20]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of DNA polymerase epsilon subunit 3 (POLE3).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA polymerase epsilon subunit 3 (POLE3).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA polymerase epsilon subunit 3 (POLE3).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA polymerase epsilon subunit 3 (POLE3).	[24]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of DNA polymerase epsilon subunit 3 (POLE3).	[25]

References

• [1] Lymphomagenic properties of a HIV p17 variant derived from a splenic marginal zone lymphoma occurred in a HIV-infected patient.Hematol Oncol. 2019 Apr;37(2):176-184. doi: 10.1002/hon.2562. Epub 2018 Nov 6.
• [2] Mechanistic insights into avian reovirus p17-modulated suppression of cell cycle CDK-cyclin complexes and enhancement of p53 and cyclin H interaction.J Biol Chem. 2018 Aug 10;293(32):12542-12562. doi: 10.1074/jbc.RA118.002341. Epub 2018 Jun 15.
• [3] Identification and characterisation of the novel amyloid-beta peptide-induced protein p17.FEBS Lett. 2009 Oct 6;583(19):3247-53. doi: 10.1016/j.febslet.2009.09.018. Epub 2009 Sep 13.
• [4] p17 from HIV induces brain endothelial cell angiogenesis through EGFR-1-mediated cell signalling activation.Lab Invest. 2019 Feb;99(2):180-190. doi: 10.1038/s41374-018-0147-z. Epub 2018 Nov 2.
• [5] Inactivating mutations of the caspase-10 gene in gastric cancer.Oncogene. 2002 Apr 25;21(18):2919-25. doi: 10.1038/sj.onc.1205394.
• [6] Molecular characterization of human immunodeficiency virus type 1 and hepatitis C virus in paid blood donors and injection drug users in china.J Virol. 2004 Dec;78(24):13591-9. doi: 10.1128/JVI.78.24.13591-13599.2004.
• [7] A CXCR1 haplotype hampers HIV-1 matrix protein p17 biological activity.AIDS. 2014 Oct 23;28(16):2355-64. doi: 10.1097/QAD.0000000000000423.
• [8] A lymphomagenic role for HIV beyond immune suppression?.Blood. 2016 Mar 17;127(11):1403-9. doi: 10.1182/blood-2015-11-681411. Epub 2016 Jan 14.
• [9] In-depth analysis of compartmentalization of HIV-1 matrix protein p17 in PBMC and plasma.New Microbiol. 2017 Jan;40(1):58-61. Epub 2017 Jan 9.
• [10] Microarray analysis of obese women with polycystic ovary syndrome for key gene screening, key pathway identification and drug prediction.Gene. 2018 Jun 30;661:85-94. doi: 10.1016/j.gene.2018.03.079. Epub 2018 Mar 28.
• [11] Therapeutic effect of a peptide inhibitor of TGF- on pulmonary fibrosis.Cytokine. 2011 Mar;53(3):327-33. doi: 10.1016/j.cyto.2010.11.019. Epub 2010 Dec 23.
• [12] elemene inhibits oxygeninduced retinal neovascularization via promoting miR?7a and reducing VEGF expression.Mol Med Rep. 2019 Mar;19(3):2307-2316. doi: 10.3892/mmr.2019.9863. Epub 2019 Jan 15.
• [13] The genetic diversification of the HIV type 1 gag p17 gene in patients infected from a common source.AIDS Res Hum Retroviruses. 1995 Oct;11(10):1197-201. doi: 10.1089/aid.1995.11.1197.
• [14] A natural HIV p17 protein variant up-regulates the LMP-1 EBV oncoprotein and promotes the growth of EBV-infected B-lymphocytes: implications for EBV-driven lymphomagenesis in the HIV setting.Int J Cancer. 2015 Sep 15;137(6):1374-85. doi: 10.1002/ijc.29494. Epub 2015 Mar 9.
• [15] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [16] 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.
• [17] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [21] 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.
• [22] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] 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.
• [25] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.