Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHBU5DJ)

• DOT Name: Endonuclease 8-like 1 (NEIL1)
• Synonyms: EC 3.2.2.-; EC 4.2.99.18; DNA glycosylase/AP lyase Neil1; DNA-(apurinic or apyrimidinic site) lyase Neil1; Endonuclease VIII-like 1; FPG1; Nei homolog 1; NEH1; Nei-like protein 1
• Gene Name: NEIL1
• Related Disease:
  Steroid-resistant nephrotic syndrome
  Advanced cancer
  Behcet disease
  Carcinoma
  Carcinoma of esophagus
  Cholangiocarcinoma
  Colorectal neoplasm
  Common variable immunodeficiency
  Congenital contractural arachnodactyly
  Depression
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Fanconi anemia complementation group A
  Fanconi's anemia
  Fatty liver disease
  Fuchs' endothelial dystrophy
  Gastric cancer
  Gastric neoplasm
  Head-neck squamous cell carcinoma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  HIV infectious disease
  Hyperlipidemia
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Obesity
  Oral cavity squamous cell carcinoma
  Parkinson disease
  Primary sclerosing cholangitis
  Squamous cell carcinoma
  Stomach cancer
  Keratoconus
  Plasma cell myeloma
  Werner syndrome
  Hyperinsulinemia
  Non-insulin dependent diabetes
• UniProt ID: NEIL1_HUMAN
• PDB ID: 1TDH; 4NRV; 5ITQ; 5ITR; 5ITT; 5ITU; 5ITX; 5ITY; 6LWA; 6LWB; 6LWC; 6LWD; 6LWF; 6LWG; 6LWH; 6LWI; 6LWJ; 6LWK; 6LWL; 6LWM; 6LWN; 6LWO; 6LWP; 6LWQ; 6LWR; 7TMX; 8FTJ
• EC Number: 3.2.2.-; 4.2.99.18
• Pfam ID: PF01149 ; PF09292
• Sequence:
  MPEGPELHLASQFVNEACRALVFGGCVEKSSVSRNPEVPFESSAYRISASARGKELRLIL
  SPLPGAQPQQEPLALVFRFGMSGSFQLVPREELPRHAHLRFYTAPPGPRLALCFVDIRRF
  GRWDLGGKWQPGRGPCVLQEYQQFRENVLRNLADKAFDRPICEALLDQRFFNGIGNYLRA
  EILYRLKIPPFEKARSVLEALQQHRPSPELTLSQKIRTKLQNPDLLELCHSVPKEVVQLG
  GKGYGSESGEEDFAAFRAWLRCYGMPGMSSLQDRHGRTIWFQGDPGPLAPKGRKSRKKKS
  KATQLSPEDRVEDALPPSKAPSRTRRAKRDLPKRTATQRPEGTSLQQDPEAPTVPKKGRR
  KGRQAASGHCRPRKVKADIPSLEPEGTSAS
• Function: Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Acts as a DNA glycosylase that recognizes and removes damaged bases. Has a preference for oxidized pyrimidines, such as thymine glycol, formamidopyrimidine (Fapy) and 5-hydroxyuracil. Has marginal activity towards 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. Has DNA glycosylase/lyase activity towards mismatched uracil and thymine, in particular in U:C and T:C mismatches. Specifically binds 5-hydroxymethylcytosine (5hmC), suggesting that it acts as a specific reader of 5hmC.
• Tissue Specificity: Ubiquitous.
• 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)
  Defective Base Excision Repair Associated with NEIL1 (R-HSA-9616334)
  Recognition and association of DNA glycosylase with site containing an affected pyrimidine (R-HSA-110328)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Steroid-resistant nephrotic syndrome	DISVEBC9	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Behcet disease	DISSYMBS	Strong	Genetic Variation	[3]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Genetic Variation	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Genetic Variation	[6]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[7]
Common variable immunodeficiency	DISHE7JQ	Strong	Biomarker	[8]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Genetic Variation	[6]
Depression	DIS3XJ69	Strong	Genetic Variation	[9]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[5]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Altered Expression	[10]
Fanconi's anemia	DISGW6Q8	Strong	Altered Expression	[10]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[11]
Fuchs' endothelial dystrophy	DISL7TXC	Strong	Genetic Variation	[12]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[13]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[13]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Posttranslational Modification	[14]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[16]
HIV infectious disease	DISO97HC	Strong	Biomarker	[17]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[11]
Neoplasm of esophagus	DISOLKAQ	Strong	Genetic Variation	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Posttranslational Modification	[18]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Oral cavity squamous cell carcinoma	DISQVJVA	Strong	Genetic Variation	[19]
Parkinson disease	DISQVHKL	Strong	Biomarker	[20]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Genetic Variation	[6]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[19]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[13]
Keratoconus	DISOONXH	moderate	Genetic Variation	[21]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[22]
Werner syndrome	DISZY45W	moderate	Biomarker	[23]
Hyperinsulinemia	DISIDWT6	Limited	Biomarker	[24]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Endonuclease 8-like 1 (NEIL1).	[26]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Endonuclease 8-like 1 (NEIL1).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Endonuclease 8-like 1 (NEIL1).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Endonuclease 8-like 1 (NEIL1).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Endonuclease 8-like 1 (NEIL1).	[28]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the activity of Endonuclease 8-like 1 (NEIL1).	[30]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Endonuclease 8-like 1 (NEIL1).	[31]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Endonuclease 8-like 1 (NEIL1).	[33]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Endonuclease 8-like 1 (NEIL1).	[34]

References

• [1] Exome sequencing identified MYO1E and NEIL1 as candidate genes for human autosomal recessive steroid-resistant nephrotic syndrome.Kidney Int. 2011 Aug;80(4):389-96. doi: 10.1038/ki.2011.148. Epub 2011 Jun 22.
• [2] The NEIL1 G83D germline DNA glycosylase variant induces genomic instability and cellular transformation.Oncotarget. 2017 Sep 8;8(49):85883-85895. doi: 10.18632/oncotarget.20716. eCollection 2017 Oct 17.
• [3] Whole Exome Sequencing Identifies Rare Protein-Coding Variants in Behet's Disease.Arthritis Rheumatol. 2016 May;68(5):1272-80. doi: 10.1002/art.39545.
• [4] NEIL1 p.Gln282Stop variant is predominantly localized in the cytoplasm and exhibits reduced activity in suppressing mutations.Gene. 2015 Oct 15;571(1):33-42. doi: 10.1016/j.gene.2015.06.043. Epub 2015 Jun 19.
• [5] A NEIL1 single nucleotide polymorphism (rs4462560) predicts the risk of radiation-induced toxicities in esophageal cancer patients treated with definitive radiotherapy.Cancer. 2013 Dec 1;119(23):4205-11. doi: 10.1002/cncr.28338. Epub 2013 Sep 10.
• [6] Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma.Carcinogenesis. 2009 Jul;30(7):1147-54. doi: 10.1093/carcin/bgp118. Epub 2009 May 14.
• [7] 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.
• [8] NEIL1 is a candidate gene associated with common variable immunodeficiency in a patient with a chromosome 15q24 deletion.Clin Immunol. 2017 Mar;176:71-76. doi: 10.1016/j.clim.2017.01.006. Epub 2017 Jan 14.
• [9] Association between single nucleotide polymorphisms of MUTYH, hOGG1 and NEIL1 genes, and depression.J Affect Disord. 2015 Sep 15;184:90-6. doi: 10.1016/j.jad.2015.05.044. Epub 2015 Jun 3.
• [10] The Fanconi anemia pathway promotes DNA glycosylase-dependent excision of interstrand DNA crosslinks.Environ Mol Mutagen. 2010 Jul;51(6):508-19. doi: 10.1002/em.20548.
• [11] Variable penetrance of metabolic phenotypes and development of high-fat diet-induced adiposity in NEIL1-deficient mice.Am J Physiol Endocrinol Metab. 2011 Apr;300(4):E724-34. doi: 10.1152/ajpendo.00387.2010. Epub 2011 Feb 1.
• [12] Variation in DNA Base Excision Repair Genes in Fuchs Endothelial Corneal Dystrophy.Med Sci Monit. 2015 Sep 21;21:2809-27. doi: 10.12659/MSM.894273.
• [13] Inactivating mutations of the human base excision repair gene NEIL1 in gastric cancer.Carcinogenesis. 2004 Dec;25(12):2311-7. doi: 10.1093/carcin/bgh267. Epub 2004 Aug 19.
• [14] Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma.Oncogene. 2012 Dec 6;31(49):5108-16. doi: 10.1038/onc.2011.660. Epub 2012 Jan 30.
• [15] Hepatitis C virus induces oxidative stress, DNA damage and modulates the DNA repair enzyme NEIL1.J Gastroenterol Hepatol. 2010 Mar;25(3):627-34. doi: 10.1111/j.1440-1746.2009.06128.x. Epub 2010 Jan 14.
• [16] Mechanisms underlying aflatoxin-associated mutagenesis - Implications in carcinogenesis.DNA Repair (Amst). 2019 May;77:76-86. doi: 10.1016/j.dnarep.2019.03.004. Epub 2019 Mar 7.
• [17] The base excision repair pathway is required for efficient lentivirus integration.PLoS One. 2011 Mar 23;6(3):e17862. doi: 10.1371/journal.pone.0017862.
• [18] A critical re-assessment of DNA repair gene promoter methylation in non-small cell lung carcinoma.Sci Rep. 2014 Feb 26;4:4186. doi: 10.1038/srep04186.
• [19] 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.
• [20] Nei-like 1 inhibition results in motor dysfunction and promotes inflammation in Parkinson's disease mice model.Biochem Biophys Res Commun. 2020 Jan 1;521(1):245-251. doi: 10.1016/j.bbrc.2019.10.118. Epub 2019 Oct 22.
• [21] Polymorphism of the DNA base excision repair genes in keratoconus.Int J Mol Sci. 2014 Oct 29;15(11):19682-99. doi: 10.3390/ijms151119682.
• [22] Aberrant hyperediting of the myeloma transcriptome by ADAR1 confers oncogenicity and is a marker of poor prognosis.Blood. 2018 Sep 20;132(12):1304-1317. doi: 10.1182/blood-2018-02-832576. Epub 2018 Jul 30.
• [23] Werner syndrome (WRN) DNA helicase and base excision repair (BER) factors maintain endothelial homeostasis.DNA Repair (Amst). 2019 Jan;73:17-27. doi: 10.1016/j.dnarep.2018.10.005. Epub 2018 Oct 28.
• [24] The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase.Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1864-9. doi: 10.1073/pnas.0507444103. Epub 2006 Jan 30.
• [25] Prevalence of the DNA repair enzyme-NEIL1 gene mutation in patients with type 2 diabetes in the Turkish population.J Endocrinol Invest. 2012 Apr;35(4):401-6. doi: 10.3275/8017. Epub 2011 Oct 6.
• [26] 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.
• [27] 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.
• [28] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [29] 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.
• [30] Specific Inhibition of NEIL-initiated repair of oxidized base damage in human genome by copper and iron: potential etiological linkage to neurodegenerative diseases. J Biol Chem. 2010 Sep 10;285(37):28812-25. doi: 10.1074/jbc.M110.126664. Epub 2010 Jul 9.
• [31] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [32] 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.
• [33] 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.
• [34] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.