Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBCI2NS)

• DOT Name: Endonuclease 8-like 3 (NEIL3)
• Synonyms: EC 3.2.2.-; EC 4.2.99.18; DNA glycosylase FPG2; DNA glycosylase/AP lyase Neil3; Endonuclease VIII-like 3; Nei-like protein 3
• Gene Name: NEIL3
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Differentiated thyroid carcinoma
  Fanconi's anemia
  Nephritis
  Ataxia-telangiectasia
  Neoplasm
  Advanced cancer
  Astrocytoma
  Myocardial infarction
  Non-insulin dependent diabetes
• UniProt ID: NEIL3_HUMAN
• PDB ID: 7JL5; 7TMY
• EC Number: 3.2.2.-; 4.2.99.18
• Pfam ID: PF06831 ; PF06839 ; PF00641
• Sequence:
  MVEGPGCTLNGEKIRARVLPGQAVTGVRGSALRSLQGRALRLAASTVVVSPQAAALNNDS
  SQNVLSLFNGYVYSGVETLGKELFMYFGPKALRIHFGMKGFIMINPLEYKYKNGASPVLE
  VQLTKDLICFFDSSVELRNSMESQQRIRMMKELDVCSPEFSFLRAESEVKKQKGRMLGDV
  LMDQNVLPGVGNIIKNEALFDSGLHPAVKVCQLTDEQIHHLMKMIRDFSILFYRCRKAGL
  ALSKHYKVYKRPNCGQCHCRITVCRFGDNNRMTYFCPHCQKENPQHVDICKLPTRNTIIS
  WTSSRVDHVMDSVARKSEEHWTCVVCTLINKPSSKACDACLTSRPIDSVLKSEENSTVFS
  HLMKYPCNTFGKPHTEVKINRKTAFGTTTLVLTDFSNKSSTLERKTKQNQILDEEFQNSP
  PASVCLNDIQHPSKKTTNDITQPSSKVNISPTISSESKLFSPAHKKPKTAQYSSPELKSC
  NPGYSNSELQINMTDGPRTLNPDSPRCSKHNRLCILRVVGKDGENKGRQFYACPLPREAQ
  CGFFEWADLSFPFCNHGKRSTMKTVLKIGPNNGKNFFVCPLGKEKQCNFFQWAENGPGIK
  IIPGC
• Function: DNA glycosylase which prefers single-stranded DNA (ssDNA), or partially ssDNA structures such as bubble and fork structures, to double-stranded DNA (dsDNA). Mediates interstrand cross-link repair in response to replication stress: acts by mediating DNA glycosylase activity, cleaving one of the two N-glycosyl bonds comprising the interstrand cross-link, which avoids the formation of a double-strand break but generates an abasic site that is bypassed by translesion synthesis polymerases. In vitro, displays strong glycosylase activity towards the hydantoin lesions spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh) in both ssDNA and dsDNA; also recognizes FapyA, FapyG, 5-OHU, 5-OHC, 5-OHMH, Tg and 8-oxoA lesions in ssDNA. No activity on 8-oxoG detected. Also shows weak DNA-(apurinic or apyrimidinic site) lyase activity. In vivo, appears to be the primary enzyme involved in removing Sp and Gh from ssDNA in neonatal tissues.
• Tissue Specificity: Expressed in keratinocytes and embryonic fibroblasts (at protein level). Also detected in thymus, testis and fetal lung primary fibroblasts.
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway:
  Cleavage of the damaged pyrimidine (R-HSA-110329)
  Recognition and association of DNA glycosylase with site containing an affected purine (R-HSA-110330)
  Cleavage of the damaged purine (R-HSA-110331)
  Defective Base Excision Repair Associated with NEIL3 (R-HSA-9629232)
  NEIL3-mediated resolution of ICLs (R-HSA-9636003)
  Recognition and association of DNA glycosylase with site containing an affected pyrimidine (R-HSA-110328)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[2]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Genetic Variation	[3]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[4]
Nephritis	DISQZQ70	Strong	Biomarker	[5]
Ataxia-telangiectasia	DISP3EVR	moderate	Biomarker	[1]
Neoplasm	DISZKGEW	moderate	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[6]
Astrocytoma	DISL3V18	Limited	Altered Expression	[7]
Myocardial infarction	DIS655KI	Limited	Posttranslational Modification	[8]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[9]

23 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 Endonuclease 8-like 3 (NEIL3).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Endonuclease 8-like 3 (NEIL3).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Endonuclease 8-like 3 (NEIL3).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Endonuclease 8-like 3 (NEIL3).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Endonuclease 8-like 3 (NEIL3).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Endonuclease 8-like 3 (NEIL3).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Endonuclease 8-like 3 (NEIL3).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Endonuclease 8-like 3 (NEIL3).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Endonuclease 8-like 3 (NEIL3).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Endonuclease 8-like 3 (NEIL3).	[18]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Endonuclease 8-like 3 (NEIL3).	[19]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Endonuclease 8-like 3 (NEIL3).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Endonuclease 8-like 3 (NEIL3).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Endonuclease 8-like 3 (NEIL3).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Endonuclease 8-like 3 (NEIL3).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Endonuclease 8-like 3 (NEIL3).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Endonuclease 8-like 3 (NEIL3).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Endonuclease 8-like 3 (NEIL3).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Endonuclease 8-like 3 (NEIL3).	[27]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Endonuclease 8-like 3 (NEIL3).	[28]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Endonuclease 8-like 3 (NEIL3).	[29]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Endonuclease 8-like 3 (NEIL3).	[30]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Endonuclease 8-like 3 (NEIL3).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Endonuclease 8-like 3 (NEIL3).	[23]

References

• [1] Loss of NEIL3 DNA glycosylase markedly increases replication associated double strand breaks and enhances sensitivity to ATR inhibitor in glioblastoma cells.Oncotarget. 2017 Dec 4;8(68):112942-112958. doi: 10.18632/oncotarget.22896. eCollection 2017 Dec 22.
• [2] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [3] Polymorphisms within base and nucleotide excision repair pathways and risk of differentiated thyroid carcinoma.DNA Repair (Amst). 2016 May;41:27-31. doi: 10.1016/j.dnarep.2016.03.011. Epub 2016 Mar 31.
• [4] TRAIP is a master regulator of DNA interstrand crosslink repair.Nature. 2019 Mar;567(7747):267-272. doi: 10.1038/s41586-019-1002-0. Epub 2019 Mar 6.
• [5] Genetic cause of immune dysregulation - one gene or two?.J Clin Invest. 2016 Nov 1;126(11):4065-4067. doi: 10.1172/JCI90831. Epub 2016 Oct 17.
• [6] Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer.Oxid Med Cell Longev. 2016;2016:1546392. doi: 10.1155/2016/1546392. Epub 2016 Mar 3.
• [7] Expression signatures of DNA repair genes correlate with survival prognosis of astrocytoma patients.Tumour Biol. 2017 Apr;39(4):1010428317694552. doi: 10.1177/1010428317694552.
• [8] NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture.Cell Rep. 2017 Jan 3;18(1):82-92. doi: 10.1016/j.celrep.2016.12.009.
• [9] Identification of a genetic locus on chromosome 4q34-35 for type 2 diabetes with overweight.Exp Mol Med. 2013 Feb 8;45(2):e7. doi: 10.1038/emm.2013.5.
• [10] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [11] 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.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [17] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] 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.
• [20] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [23] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [24] 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.
• [25] 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.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [27] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [28] 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.
• [29] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [30] 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.
• [31] 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.