Details of Drug Off-Target (DOT)

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

• DOT Name: OTU domain-containing protein 3 (OTUD3)
• Synonyms: EC 3.4.19.12
• Gene Name: OTUD3
• Related Disease:
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Multiple sclerosis
  Non-small-cell lung cancer
  Ulcerative colitis
• UniProt ID: OTUD3_HUMAN
• PDB ID: 4BOU
• EC Number: 3.4.19.12
• Pfam ID: PF02338
• Sequence:
  MSRKQAAKSRPGSGSRKAEAERKRDERAARRALAKERRNRPESGGGGGCEEEFVSFANQL
  QALGLKLREVPGDGNCLFRALGDQLEGHSRNHLKHRQETVDYMIKQREDFEPFVEDDIPF
  EKHVASLAKPGTFAGNDAIVAFARNHQLNVVIHQLNAPLWQIRGTEKSSVRELHIAYRYG
  EHYDSVRRINDNSEAPAHLQTDFQMLHQDESNKREKIKTKGMDSEDDLRDEVEDAVQKVC
  NATGCSDFNLIVQNLEAENYNIESAIIAVLRMNQGKRNNAEENLEPSGRVLKQCGPLWEE
  GGSGARIFGNQGLNEGRTENNKAQASPSEENKANKNQLAKVTNKQRREQQWMEKKKRQEE
  RHRHKALESRGSHRDNNRSEAEANTQVTLVKTFAALNI
• Function: Deubiquitinating enzyme that hydrolyzes 'Lys-6'- and 'Lys-11'-linked polyubiquitin. Also hydrolyzes heterotypic (mixed and branched) and homotypic chains. Important regulator of energy metabolism. Glucose and fatty acids trigger its nuclear translocation by CBP-dependent acetylation. In the nucleus, deubiquitinates and stabilizes the nuclear receptor PPARD regulating the expression of various genes involved in glucose and lipid metabolism and oxidative phosphorylation. Also acts as a negative regulator of the ribosome quality control (RQC) by mediating deubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS20/uS10, thereby antagonizing ZNF598-mediated 40S ubiquitination.
• Reactome Pathway:
  Regulation of PTEN stability and activity (R-HSA-8948751)
  Ovarian tumor domain proteases (R-HSA-5689896)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[4]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of OTU domain-containing protein 3 (OTUD3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of OTU domain-containing protein 3 (OTUD3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of OTU domain-containing protein 3 (OTUD3).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of OTU domain-containing protein 3 (OTUD3).	[9]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of OTU domain-containing protein 3 (OTUD3).	[10]

References

• [1] The deubiquitylase OTUD3 stabilizes GRP78 and promotes lung tumorigenesis.Nat Commun. 2019 Jul 2;10(1):2914. doi: 10.1038/s41467-019-10824-7.
• [2] MicroRNA 32 promotes cell proliferation, migration, and suppresses apoptosis in colon cancer cells by targeting OTU domain containing 3.J Cell Biochem. 2019 Nov;120(11):18629-18639. doi: 10.1002/jcb.28874. Epub 2019 Jul 24.
• [3] Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
• [4] Distinct expression and prognostic value of OTU domain-containing proteins in non-small-cell lung cancer.Oncol Lett. 2019 Nov;18(5):5417-5427. doi: 10.3892/ol.2019.10883. Epub 2019 Sep 19.
• [5] Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL).Nat Genet. 2010 Apr;42(4):292-4. doi: 10.1038/ng.553. Epub 2010 Mar 14.
• [6] 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.
• [7] 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.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.