Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZTWD86)

• DOT Name: Uracil-DNA glycosylase
• Synonyms: UDG; EC 3.2.2.27
• Gene Name: UNG
• Related Disease: Hyper-IgM syndrome type 5
• UniProt ID: UNG_HUMAN
• PDB ID: 1AKZ; 1DPU; 1EMH; 1EMJ; 1Q3F; 1SSP; 1UGH; 1YUO; 2HXM; 2OXM; 2OYT; 2SSP; 3FCF; 3FCI; 3FCK; 3FCL; 3TKB; 4SKN; 5AYR; 5JK7; 6VBA; 7V7C
• EC Number: 3.2.2.27
• Pfam ID: PF03167
• Sequence:
  MIGQKTLYSFFSPSPARKRHAPSPEPAVQGTGVAGVPEESGDAAAIPAKKAPAGQEEPGT
  PPSSPLSAEQLDRIQRNKAAALLRLAARNVPVGFGESWKKHLSGEFGKPYFIKLMGFVAE
  ERKHYTVYPPPHQVFTWTQMCDIKDVKVVILGQDPYHGPNQAHGLCFSVQRPVPPPPSLE
  NIYKELSTDIEDFVHPGHGDLSGWAKQGVLLLNAVLTVRAHQANSHKERGWEQFTDAVVS
  WLNQNSNGLVFLLWGSYAQKKGSAIDRKRHHVLQTAHPSPLSVYRGFFGCRHFSKTNELL
  QKSGKKPIDWKEL
• Function: Excises uracil residues from the DNA which can arise as a result of misincorporation of dUMP residues by DNA polymerase or due to deamination of cytosine.
• Tissue Specificity: Isoform 1 is widely expressed with the highest expression in skeletal muscle, heart and testicles. Isoform 2 has the highest expression levels in tissues containing proliferating cells.
• KEGG Pathway:
  Base excision repair (hsa03410)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway: Chromatin modifications during the maternal to zygotic transition (MZT) (R-HSA-9821002)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyper-IgM syndrome type 5	DISQ328A	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Uracil-DNA glycosylase affects the response to substance of Arsenic.	[38]
Methotrexate	DM2TEOL	Approved	Uracil-DNA glycosylase increases the Chromosomal abnormalities and abnormal gene carriers ADR of Methotrexate.	[39]
Paclitaxel	DMLB81S	Approved	Uracil-DNA glycosylase affects the response to substance of Paclitaxel.	[40]
Topotecan	DMP6G8T	Approved	Uracil-DNA glycosylase affects the response to substance of Topotecan.	[40]
Floxuridine	DM04LR2	Approved	Uracil-DNA glycosylase increases the response to substance of Floxuridine.	[14]

42 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 Uracil-DNA glycosylase.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Uracil-DNA glycosylase.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Uracil-DNA glycosylase.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Uracil-DNA glycosylase.	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Uracil-DNA glycosylase.	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Uracil-DNA glycosylase.	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Uracil-DNA glycosylase.	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Uracil-DNA glycosylase.	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Uracil-DNA glycosylase.	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Uracil-DNA glycosylase.	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Uracil-DNA glycosylase.	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Uracil-DNA glycosylase.	[12]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Uracil-DNA glycosylase.	[13]
Menadione	DMSJDTY	Approved	Menadione decreases the expression of Uracil-DNA glycosylase.	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Uracil-DNA glycosylase.	[14]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Uracil-DNA glycosylase.	[15]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Uracil-DNA glycosylase.	[16]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Uracil-DNA glycosylase.	[17]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Uracil-DNA glycosylase.	[18]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Uracil-DNA glycosylase.	[19]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Uracil-DNA glycosylase.	[20]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Uracil-DNA glycosylase.	[21]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Uracil-DNA glycosylase.	[22]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Uracil-DNA glycosylase.	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Uracil-DNA glycosylase.	[23]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Uracil-DNA glycosylase.	[22]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone decreases the expression of Uracil-DNA glycosylase.	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Uracil-DNA glycosylase.	[25]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of Uracil-DNA glycosylase.	[26]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Uracil-DNA glycosylase.	[9]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Uracil-DNA glycosylase.	[15]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Uracil-DNA glycosylase.	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Uracil-DNA glycosylase.	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Uracil-DNA glycosylase.	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Uracil-DNA glycosylase.	[30]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Uracil-DNA glycosylase.	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Uracil-DNA glycosylase.	[9]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Uracil-DNA glycosylase.	[33]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Uracil-DNA glycosylase.	[34]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Uracil-DNA glycosylase.	[35]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the expression of Uracil-DNA glycosylase.	[36]
Indirubin-3'-monoxime	DMLRQH0	Investigative	Indirubin-3'-monoxime increases the expression of Uracil-DNA glycosylase.	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
G1	DMTV42K	Phase 1/2	G1 decreases the phosphorylation of Uracil-DNA glycosylase.	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Uracil-DNA glycosylase.	[31]

References

• [1] Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol. 2003 Oct;4(10):1023-8. doi: 10.1038/ni974. Epub 2003 Sep 7.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [10] Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] 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.
• [13] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [14] Fluorodeoxyuridine modulates cellular expression of the DNA base excision repair enzyme uracil-DNA glycosylase. Cancer Res. 2006 Sep 1;66(17):8829-37. doi: 10.1158/0008-5472.CAN-06-0540.
• [15] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [16] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [17] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [18] 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.
• [19] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [20] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [21] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [22] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [23] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [24] The sunless tanning agent dihydroxyacetone induces stress response gene expression and signaling in cultured human keratinocytes and reconstructed epidermis. Redox Biol. 2020 Sep;36:101594. doi: 10.1016/j.redox.2020.101594. Epub 2020 May 29.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
• [27] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [28] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [29] BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res. 2014 Feb 15;20(4):912-25.
• [30] 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.
• [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.
• [32] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [33] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [34] 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.
• [35] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [36] The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth. Free Radic Biol Med. 2009 Jan 15;46(2):220-31.
• [37] The effects of indirubin-3'-monoxime, a novel AHR ligand, on stress and toxicity-related gene/protein expression in human U937 cells undergoing differentiation and activation. J Immunotoxicol. 2006 Jan 1;3(1):1-10.
• [38] m6A demethylation of cytidine deaminase APOBEC3B mRNA orchestrates arsenic-induced mutagenesis. J Biol Chem. 2022 Feb;298(2):101563. doi: 10.1016/j.jbc.2022.101563. Epub 2022 Jan 6.
• [39] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [40] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [41] Fluorodeoxyuridine modulates cellular expression of the DNA base excision repair enzyme uracil-DNA glycosylase. Cancer Res. 2006 Sep 1;66(17):8829-37. doi: 10.1158/0008-5472.CAN-06-0540.