Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCMWUT6)

• DOT Name: DNA polymerase epsilon subunit 4 (POLE4)
• Synonyms: DNA polymerase II subunit 4; DNA polymerase epsilon subunit p12
• Gene Name: POLE4
• Related Disease:
  Hyperglycemia
  Malaria
  Retinopathy
  Acute otitis media
  Adult respiratory distress syndrome
  Adult T-cell leukemia/lymphoma
  Bone osteosarcoma
  Cystic fibrosis
  Glioma
  Leukemia
  Neoplasm
  Non-hodgkin lymphoma
  Osteosarcoma
  Otitis media
  Pathologic nystagmus
  Rift valley fever
  T-cell leukaemia
  Human T-lymphotropic virus 1 infectious disease
  Acute myelogenous leukaemia
  Adult glioblastoma
  Glioblastoma multiforme
  Polyposis
  T-cell acute lymphoblastic leukaemia
• UniProt ID: DPOE4_HUMAN
• Pfam ID: PF00808
• Sequence:
  MAAAAAAGSGTPREEEGPAGEAAASQPQAPTSVPGARLSRLPLARVKALVKADPDVTLAG
  QEAIFILARAAELFVETIAKDAYCCAQQGKRKTLQRRDLDNAIEAVDEFAFLEGTLD
• 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

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperglycemia	DIS0BZB5	Definitive	Biomarker	[1]
Malaria	DISQ9Y50	Definitive	Biomarker	[2]
Retinopathy	DISB4B0F	Definitive	Biomarker	[3]
Acute otitis media	DISL8D8G	Strong	Biomarker	[4]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[5]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[6]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[7]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[8]
Glioma	DIS5RPEH	Strong	Altered Expression	[9]
Leukemia	DISNAKFL	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[12]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[7]
Otitis media	DISGZDUO	Strong	Biomarker	[4]
Pathologic nystagmus	DIS1QSPO	Strong	Biomarker	[13]
Rift valley fever	DISG6CM2	Strong	Genetic Variation	[14]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[15]
Human T-lymphotropic virus 1 infectious disease	DISN5C4M	Disputed	Biomarker	[16]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[17]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[18]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[18]
Polyposis	DISZSPOK	Limited	Biomarker	[19]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Altered Expression	[20]

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 DNA polymerase epsilon subunit 4 (POLE4).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of DNA polymerase epsilon subunit 4 (POLE4).	[31]

10 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 DNA polymerase epsilon subunit 4 (POLE4).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA polymerase epsilon subunit 4 (POLE4).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA polymerase epsilon subunit 4 (POLE4).	[24]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DNA polymerase epsilon subunit 4 (POLE4).	[25]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA polymerase epsilon subunit 4 (POLE4).	[26]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of DNA polymerase epsilon subunit 4 (POLE4).	[27]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DNA polymerase epsilon subunit 4 (POLE4).	[26]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of DNA polymerase epsilon subunit 4 (POLE4).	[28]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of DNA polymerase epsilon subunit 4 (POLE4).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA polymerase epsilon subunit 4 (POLE4).	[30]

References

• [1] Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus.NMR Biomed. 2018 May;31(5):e3910. doi: 10.1002/nbm.3910. Epub 2018 Mar 13.
• [2] Low genetic diversity and functional constraint in loci encoding Plasmodium vivax P12 and P38 proteins in the Colombian population.Malar J. 2014 Feb 18;13:58. doi: 10.1186/1475-2875-13-58.
• [3] 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.
• [4] Pathological features in the LmnaDhe/+ mutant mouse provide a novel model of human otitis media and laminopathies.Am J Pathol. 2012 Sep;181(3):761-74. doi: 10.1016/j.ajpath.2012.05.031. Epub 2012 Jul 20.
• [5] Size-dependent anti-inflammatory activity of a peptide-gold nanoparticle hybrid in vitro and in a mouse model of acute lung injury.Acta Biomater. 2019 Feb;85:203-217. doi: 10.1016/j.actbio.2018.12.046. Epub 2018 Dec 28.
• [6] Palmitoylation and p8-mediated human T-cell leukemia virus type 1 transmission.J Virol. 2014 Feb;88(4):2319-22. doi: 10.1128/JVI.03444-13. Epub 2013 Nov 27.
• [7] Overexpression through amplification of genes in chromosome region 17p11.2 approximately p12 in high-grade osteosarcoma.Cancer Genet Cytogenet. 2004 Jul 1;152(1):8-14. doi: 10.1016/j.cancergencyto.2003.09.024.
• [8] Molecular characterization of pyocin S3, a novel S-type pyocin from Pseudomonas aeruginosa.J Biol Chem. 1995 Apr 14;270(15):8920-7. doi: 10.1074/jbc.270.15.8920.
• [9] TNF receptor-associated factor 6 regulates proliferation, apoptosis, and invasion of glioma cells.Mol Cell Biochem. 2013 May;377(1-2):87-96. doi: 10.1007/s11010-013-1573-2. Epub 2013 Jan 29.
• [10] The N-terminus of murine leukaemia virus p12 protein is required for mature core stability.PLoS Pathog. 2014 Oct 30;10(10):e1004474. doi: 10.1371/journal.ppat.1004474. eCollection 2014 Oct.
• [11] Loss of the p12 subunit of DNA polymerase delta leads to a defect in HR and sensitization to PARP inhibitors.DNA Repair (Amst). 2019 Jan;73:64-70. doi: 10.1016/j.dnarep.2018.11.003. Epub 2018 Nov 13.
• [12] Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas.Blood. 2002 Jun 1;99(11):4094-9. doi: 10.1182/blood.v99.11.4094.
• [13] Vestibular cerebellar evoked potentials in humans and their modulation during optokinetic stimulation.J Neurophysiol. 2018 Dec 1;120(6):3099-3109. doi: 10.1152/jn.00502.2018. Epub 2018 Oct 17.
• [14] Ability of a mutagenized virus variant to protect young lambs from Rift Valley fever.Am J Vet Res. 1991 Jan;52(1):50-5.
• [15] Simian T cell leukemia virus type I from naturally infected feral monkeys from central and west Africa encodes a 91-amino acid p12 (ORF-I) protein as opposed to a 99-amino acid protein encoded by HTLV type I from humans.AIDS Res Hum Retroviruses. 1997 Mar 20;13(5):425-32. doi: 10.1089/aid.1997.13.425.
• [16] Human T cell lymphotropic virus type I (HTLV-I) p12I is dispensable for HTLV-I transmission and maintenance of infection in vivo.AIDS Res Hum Retroviruses. 2004 Oct;20(10):1092-9. doi: 10.1089/aid.2004.20.1092.
• [17] The t(10;11) translocation in acute myeloid leukemia (M5) consistently fuses the leucine zipper motif of AF10 onto the HRX gene.Blood. 1995 Sep 15;86(6):2073-6.
• [18] Pharmacological effects of asiatic acid in glioblastoma cells under hypoxia.Mol Cell Biochem. 2017 Jun;430(1-2):179-190. doi: 10.1007/s11010-017-2965-5. Epub 2017 Feb 15.
• [19] Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.Int J Cancer. 2015 Jul 15;137(2):320-31. doi: 10.1002/ijc.29396. Epub 2015 Jan 20.
• [20] Multipoint interphase FISH in childhood T-acute lymphoblastic leukemia detects subpopulations that carry different chromosome 3 aberrations.Cancer Genet Cytogenet. 2007 Jan 1;172(1):54-60. doi: 10.1016/j.cancergencyto.2006.08.004.
• [21] 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.
• [22] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [23] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [26] 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.
• [27] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [28] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [29] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [30] Exposure to environmental bisphenol A inhibits HTR-8/SVneo cell migration and invasion. J Biomed Res. 2020 Jun 30;34(5):369-378. doi: 10.7555/JBR.34.20200013.
• [31] 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.