Details of Drug Off-Target (DOT)

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

• DOT Name: Tyrosyl-DNA phosphodiesterase 1 (TDP1)
• Synonyms: Tyr-DNA phosphodiesterase 1; EC 3.1.4.-
• Gene Name: TDP1
• Related Disease:
  Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
• UniProt ID: TYDP1_HUMAN
• PDB ID: 1JY1 ; 1MU7 ; 1MU9 ; 1NOP ; 1QZQ ; 1RFF ; 1RFI ; 1RG1 ; 1RG2 ; 1RGT ; 1RGU ; 1RH0 ; 5NW9 ; 5NWA ; 6DHU ; 6DIE ; 6DIH ; 6DIM ; 6DJD ; 6DJE ; 6DJF ; 6DJG ; 6DJH ; 6DJI ; 6DJJ ; 6MJ5 ; 6MYZ ; 6MZ0 ; 6N0D ; 6N0N ; 6N0O ; 6N0R ; 6N17 ; 6N19 ; 6W4R ; 6W7J ; 6W7K ; 6W7L ; 7UFY ; 7UFZ ; 8CVQ ; 8CW2
• EC Number: 3.1.4.-
• Pfam ID: PF06087
• Sequence:
  MSQEGDYGRWTISSSDESEEEKPKPDKPSTSSLLCARQGAANEPRYTCSEAQKAAHKRKI
  SPVKFSNTDSVLPPKRQKSGSQEDLGWCLSSSDDELQPEMPQKQAEKVVIKKEKDISAPN
  DGTAQRTENHGAPACHRLKEEEDEYETSGEGQDIWDMLDKGNPFQFYLTRVSGVKPKYNS
  GALHIKDILSPLFGTLVSSAQFNYCFDVDWLVKQYPPEFRKKPILLVHGDKREAKAHLHA
  QAKPYENISLCQAKLDIAFGTHHTKMMLLLYEEGLRVVIHTSNLIHADWHQKTQGIWLSP
  LYPRIADGTHKSGESPTHFKADLISYLMAYNAPSLKEWIDVIHKHDLSETNVYLIGSTPG
  RFQGSQKDNWGHFRLKKLLKDHASSMPNAESWPVVGQFSSVGSLGADESKWLCSEFKESM
  LTLGKESKTPGKSSVPLYLIYPSVENVRTSLEGYPAGGSLPYSIQTAEKQNWLHSYFHKW
  SAETSGRSNAMPHIKTYMRPSPDFSKIAWFLVTSANLSKAAWGALEKNGTQLMIRSYELG
  VLFLPSAFGLDSFKVKQKFFAGSQEPMATFPVPYDLPPELYGSKDRPWIWNIPYVKAPDT
  HGNMWVPS
• Function: DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate.
• Tissue Specificity: Ubiquitously expressed. Similar expression throughout the central nervous system (whole brain, amygdala, caudate nucleus, cerebellum, cerebral cortex, frontal lobe, hippocampus, medulla oblongata, occipital lobe, putamen, substantia nigra, temporal lobe, thalamus, nucleus accumbens and spinal cord) and increased expression in testis and thymus.
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway: Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	DISZGP6L	Strong	Autosomal recessive	[1]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Disputed	Autosomal recessive	[2]

18 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 Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[10]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[11]
Amantadine	DMS3YE9	Approved	Amantadine decreases the activity of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Tyrosyl-DNA phosphodiesterase 1 (TDP1).	[22]

References

• [1] Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet. 2002 Oct;32(2):267-72. doi: 10.1038/ng987. Epub 2002 Sep 16.
• [2] A genomics approach to male infertility. Genet Med. 2020 Dec;22(12):1967-1975. doi: 10.1038/s41436-020-0916-0. Epub 2020 Jul 28.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [11] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [12] Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors. Bioorg Chem. 2018 Feb;76:392-399. doi: 10.1016/j.bioorg.2017.12.005. Epub 2017 Dec 9.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] 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.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [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] 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.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] 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.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.