Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV6JEON)

• DOT Name: Endonuclease 8-like 2 (NEIL2)
• Synonyms: EC 3.2.2.-; EC 4.2.99.18; DNA glycosylase/AP lyase Neil2; DNA-(apurinic or apyrimidinic site) lyase Neil2; Endonuclease VIII-like 2; Nei homolog 2; NEH2; Nei-like protein 2
• Gene Name: NEIL2
• Related Disease:
  Colorectal neoplasm
  Congenital diaphragmatic hernia
  Gastric cancer
  Lung cancer
  Lung carcinoma
  Neoplasm
  Oral cavity squamous cell carcinoma
  Oropharyngeal cancer
  Oropharyngeal carcinoma
  Polycystic ovarian syndrome
  Squamous cell carcinoma
  Stomach cancer
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Hepatitis C virus infection
  Hepatocellular carcinoma
• UniProt ID: NEIL2_HUMAN
• EC Number: 3.2.2.-; 4.2.99.18
• Pfam ID: PF06831
• Sequence:
  MPEGPLVRKFHHLVSPFVGQQVVKTGGSSKKLQPASLQSLWLQDTQVHGKKLFLRFDLDE
  EMGPPGSSPTPEPPQKEVQKEGAADPKQVGEPSGQKTLDGSSRSAELVPQGEDDSEYLER
  DAPAGDAGRWLRVSFGLFGSVWVNDFSRAKKANKRGDWRDPSPRLVLHFGGGGFLAFYNC
  QLSWSSSPVVTPTCDILSEKFHRGQALEALGQAQPVCYTLLDQRYFSGLGNIIKNEALYR
  AGIHPLSLGSVLSASRREVLVDHVVEFSTAWLQGKFQGRPQHTQVYQKEQCPAGHQVMKE
  AFGPEDGLQRLTWWCPQCQPQLSEEPEQCQFS
• Function: Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Has DNA glycosylase activity towards 5-hydroxyuracil and other oxidized derivatives of cytosine with a preference for mismatched double-stranded DNA (DNA bubbles). Has low or no DNA glycosylase activity towards thymine glycol, 2-hydroxyadenine, hypoxanthine and 8-oxoguanine. Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates.
• Tissue Specificity: Detected in testis, skeletal muscle, heart, brain, placenta, lung, pancreas, kidney and liver.
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway:
  Cleavage of the damaged pyrimidine (R-HSA-110329)
  APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway (R-HSA-5649702)
  Recognition and association of DNA glycosylase with site containing an affected pyrimidine (R-HSA-110328)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[1]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[3]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[3]
Oral cavity squamous cell carcinoma	DISQVJVA	Strong	Genetic Variation	[5]
Oropharyngeal cancer	DISDAMTJ	Strong	Genetic Variation	[5]
Oropharyngeal carcinoma	DIS7K3AI	Strong	Genetic Variation	[5]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[6]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[5]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[7]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[8]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[8]
Hepatitis C virus infection	DISQ0M8R	Limited	Genetic Variation	[9]
Hepatocellular carcinoma	DIS0J828	Limited	Genetic Variation	[9]

8 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 Endonuclease 8-like 2 (NEIL2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Endonuclease 8-like 2 (NEIL2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Endonuclease 8-like 2 (NEIL2).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Endonuclease 8-like 2 (NEIL2).	[14]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Endonuclease 8-like 2 (NEIL2).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Endonuclease 8-like 2 (NEIL2).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Endonuclease 8-like 2 (NEIL2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Endonuclease 8-like 2 (NEIL2).	[18]

3 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 8-like 2 (NEIL2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Endonuclease 8-like 2 (NEIL2).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Endonuclease 8-like 2 (NEIL2).	[19]

References

• [1] Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition. BMC Cancer. 2006 Oct 9;6:243. doi: 10.1186/1471-2407-6-243.
• [2] Prenatal diagnosis of two fetuses with deletions of 8p23.1, critical region for congenital diaphragmatic hernia and heart defects.Am J Med Genet A. 2013 Jul;161A(7):1755-8. doi: 10.1002/ajmg.a.35965. Epub 2013 May 21.
• [3] Polymorphisms in NEIL-2, APE-1, CYP2E1 and MDM2 Genes are Independent Predictors of Gastric Cancer Risk in a Northern Jiangsu Population (China).J Nanosci Nanotechnol. 2015 Jul;15(7):4815-28. doi: 10.1166/jnn.2015.10028.
• [4] NEIL2 protects against oxidative DNA damage induced by sidestream smoke in human cells.PLoS One. 2014 Mar 3;9(3):e90261. doi: 10.1371/journal.pone.0090261. eCollection 2014.
• [5] Functional variants of the NEIL1 and NEIL2 genes and risk and progression of squamous cell carcinoma of the oral cavity and oropharynx.Clin Cancer Res. 2008 Jul 1;14(13):4345-52. doi: 10.1158/1078-0432.CCR-07-5282.
• [6] Phenotype and Tissue Expression as a Function of Genetic Risk in Polycystic Ovary Syndrome.PLoS One. 2017 Jan 9;12(1):e0168870. doi: 10.1371/journal.pone.0168870. eCollection 2017.
• [7] PEG-functionalized zinc oxide nanoparticles induce apoptosis in breast cancer cells through reactive oxygen species-dependent impairment of DNA damage repair enzyme NEIL2.Free Radic Biol Med. 2017 Feb;103:35-47. doi: 10.1016/j.freeradbiomed.2016.11.048. Epub 2016 Dec 7.
• [8] DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.PLoS Genet. 2014 Apr 3;10(4):e1004256. doi: 10.1371/journal.pgen.1004256. eCollection 2014 Apr.
• [9] Polymorphisms of base-excision repair genes and the hepatocarcinogenesis.Gene. 2018 Oct 30;675:62-68. doi: 10.1016/j.gene.2018.06.056. Epub 2018 Jun 20.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] 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.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [15] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [16] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [17] 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.
• [18] 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.
• [19] 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.