Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKXT1D7)

• DOT Name: Ubiquitin carboxyl-terminal hydrolase 1
• Synonyms: EC 3.4.19.12; Deubiquitinating enzyme 1; hUBP; Ubiquitin thioesterase 1; Ubiquitin-specific-processing protease 1
• Gene Name: USP1
• Related Disease: Tourette syndrome
• UniProt ID: UBP1_HUMAN
• PDB ID: 6DO5; 7AY0; 7AY1; 7AY2; 7ZH3; 7ZH4; 8A9J; 8A9K
• EC Number: 3.4.19.12
• Pfam ID: PF00443
• Sequence:
  MPGVIPSESNGLSRGSPSKKNRLSLKFFQKKETKRALDFTDSQENEEKASEYRASEIDQV
  VPAAQSSPINCEKRENLLPFVGLNNLGNTCYLNSILQVLYFCPGFKSGVKHLFNIISRKK
  EALKDEANQKDKGNCKEDSLASYELICSLQSLIISVEQLQASFLLNPEKYTDELATQPRR
  LLNTLRELNPMYEGYLQHDAQEVLQCILGNIQETCQLLKKEEVKNVAELPTKVEEIPHPK
  EEMNGINSIEMDSMRHSEDFKEKLPKGNGKRKSDTEFGNMKKKVKLSKEHQSLEENQRQT
  RSKRKATSDTLESPPKIIPKYISENESPRPSQKKSRVKINWLKSATKQPSILSKFCSLGK
  ITTNQGVKGQSKENECDPEEDLGKCESDNTTNGCGLESPGNTVTPVNVNEVKPINKGEEQ
  IGFELVEKLFQGQLVLRTRCLECESLTERREDFQDISVPVQEDELSKVEESSEISPEPKT
  EMKTLRWAISQFASVERIVGEDKYFCENCHHYTEAERSLLFDKMPEVITIHLKCFAASGL
  EFDCYGGGLSKINTPLLTPLKLSLEEWSTKPTNDSYGLFAVVMHSGITISSGHYTASVKV
  TDLNSLELDKGNFVVDQMCEIGKPEPLNEEEARGVVENYNDEEVSIRVGGNTQPSKVLNK
  KNVEAIGLLGGQKSKADYELYNKASNPDKVASTAFAENRNSETSDTTGTHESDRNKESSD
  QTGINISGFENKISYVVQSLKEYEGKWLLFDDSEVKVTEEKDFLNSLSPSTSPTSTPYLL
  FYKKL
• Function: Negative regulator of DNA damage repair which specifically deubiquitinates monoubiquitinated FANCD2. Also involved in PCNA-mediated translesion synthesis (TLS) by deubiquitinating monoubiquitinated PCNA. Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity.
• KEGG Pathway: Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Fanconi Anemia Pathway (R-HSA-6783310)
  Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tourette syndrome	DISX9D54	No Known	Unknown	[1]

16 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 Ubiquitin carboxyl-terminal hydrolase 1.	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[11]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[17]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Ubiquitin carboxyl-terminal hydrolase 1.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Ubiquitin carboxyl-terminal hydrolase 1.	[6]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Ubiquitin carboxyl-terminal hydrolase 1.	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ubiquitin carboxyl-terminal hydrolase 1.	[6]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Ubiquitin carboxyl-terminal hydrolase 1.	[6]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Ubiquitin carboxyl-terminal hydrolase 1.	[18]

References

• [1] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [13] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [19] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.