Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPQXPT1)

• DOT Name: Endonuclease III-like protein 1 (NTHL1)
• Synonyms: hNTH1; EC 3.2.2.-; EC 4.2.99.18; Bifunctional DNA N-glycosylase/DNA-(apurinic or apyrimidinic site) lyase; DNA glycosylase/AP lyase
• Gene Name: NTHL1
• Related Disease:
  Familial adenomatous polyposis 3
  NTHL1-deficiency tumor predisposition syndrome
  Adenoma
  Advanced cancer
  Attenuated familial adenomatous polyposis
  Chromosomal disorder
  Colorectal adenoma
  Colorectal carcinoma
  Familial adenomatous polyposis
  Familial adenomatous polyposis 1
  Familial adenomatous polyposis 2
  Gastric cancer
  Lung cancer
  Lung carcinoma
  Neoplasm
  Stomach cancer
  Carcinoma
  Fanconi anemia complementation group D2
  Intellectual disability, autosomal recessive 1
  Polyp of large intestine
  Thyroid gland follicular carcinoma
  Hyperplastic polyposis syndrome
  Tuberous sclerosis 2
• UniProt ID: NTH_HUMAN
• PDB ID: 7RDS; 7RDT
• EC Number: 3.2.2.-; 4.2.99.18
• Pfam ID: PF00633 ; PF00730
• Sequence:
  MCSPQESGMTALSARMLTRSRSLGPGAGPRGCREEPGPLRRREAAAEARKSHSPVKRPRK
  AQRLRVAYEGSDSEKGEGAEPLKVPVWEPQDWQQQLVNIRAMRNKKDAPVDHLGTEHCYD
  SSAPPKVRRYQVLLSLMLSSQTKDQVTAGAMQRLRARGLTVDSILQTDDATLGKLIYPVG
  FWRSKVKYIKQTSAILQQHYGGDIPASVAELVALPGVGPKMAHLAMAVAWGTVSGIAVDT
  HVHRIANRLRWTKKATKSPEETRAALEEWLPRELWHEINGLLVGFGQQTCLPVHPRCHAC
  LNQALCPAAQGL
• Function: Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage. The DNA N-glycosylase activity releases the damaged DNA base from DNA by cleaving the N-glycosidic bond, leaving an AP site. The AP-lyase activity cleaves the phosphodiester bond 3' to the AP site by a beta-elimination. Primarily recognizes and repairs oxidative base damage of pyrimidines. Has also 8-oxo-7,8-dihydroguanine (8-oxoG) DNA glycosylase activity. Acts preferentially on DNA damage opposite guanine residues in DNA. Is able to process lesions in nucleosomes without requiring or inducing nucleosome disruption.
• Tissue Specificity: Widely expressed with highest levels in heart and lowest levels in lung and liver.
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway:
  Cleavage of the damaged pyrimidine (R-HSA-110329)
  Displacement of DNA glycosylase by APEX1 (R-HSA-110357)
  Defective NTHL1 substrate processing (R-HSA-9630221)
  Defective NTHL1 substrate binding (R-HSA-9630222)
  Recognition and association of DNA glycosylase with site containing an affected pyrimidine (R-HSA-110328)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial adenomatous polyposis 3	DISEKCBN	Definitive	Autosomal recessive	[1]
NTHL1-deficiency tumor predisposition syndrome	DISNQHXW	Definitive	Autosomal recessive	[2]
Adenoma	DIS78ZEV	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Attenuated familial adenomatous polyposis	DISGMTLG	Strong	Biomarker	[5]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[6]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Familial adenomatous polyposis	DISW53RE	Strong	Genetic Variation	[4]
Familial adenomatous polyposis 1	DISM44VR	Strong	Biomarker	[8]
Familial adenomatous polyposis 2	DIS62W3Y	Strong	Genetic Variation	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[11]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[10]
Carcinoma	DISH9F1N	moderate	Genetic Variation	[12]
Fanconi anemia complementation group D2	DISC76W3	moderate	Biomarker	[13]
Intellectual disability, autosomal recessive 1	DISINB3A	moderate	Biomarker	[13]
Polyp of large intestine	DISRE1MK	moderate	Genetic Variation	[12]
Thyroid gland follicular carcinoma	DISFK2QT	moderate	Biomarker	[14]
Hyperplastic polyposis syndrome	DISVLOYP	Limited	Genetic Variation	[7]
Tuberous sclerosis 2	DISR6GKZ	Limited	Altered Expression	[15]

5 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 III-like protein 1 (NTHL1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Endonuclease III-like protein 1 (NTHL1).	[24]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Endonuclease III-like protein 1 (NTHL1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Endonuclease III-like protein 1 (NTHL1).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Endonuclease III-like protein 1 (NTHL1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Endonuclease III-like protein 1 (NTHL1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Endonuclease III-like protein 1 (NTHL1).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Endonuclease III-like protein 1 (NTHL1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Endonuclease III-like protein 1 (NTHL1).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Endonuclease III-like protein 1 (NTHL1).	[21]
Dactinomycin	DM2YGNW	Approved	Dactinomycin decreases the expression of Endonuclease III-like protein 1 (NTHL1).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Endonuclease III-like protein 1 (NTHL1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Endonuclease III-like protein 1 (NTHL1).	[27]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Endonuclease III-like protein 1 (NTHL1).	[29]

References

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• [12] Defective repair capacity of variant proteins of the DNA glycosylase NTHL1 for 5-hydroxyuracil, an oxidation product of cytosine.Free Radic Biol Med. 2019 Feb 1;131:264-273. doi: 10.1016/j.freeradbiomed.2018.12.010. Epub 2018 Dec 12.
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• [14] Distinct pattern of oxidative DNA damage and DNA repair in follicular thyroid tumours.J Mol Endocrinol. 2012 Mar 29;48(3):193-202. doi: 10.1530/JME-11-0119. Print 2012 Jun.
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• [18] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [19] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] 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.
• [25] 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.
• [26] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] 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.
• [29] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.