Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTUJQJ1)

• DOT Name: Small ubiquitin-related modifier 3 (SUMO3)
• Synonyms: SUMO-3; SMT3 homolog 1; SUMO-2; Ubiquitin-like protein SMT3A; Smt3A
• Gene Name: SUMO3
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Acute megakaryoblastic leukemia
  Bacillary dysentery
  Cardiac failure
  Cardiomyopathy
  Cerebral infarction
  Congestive heart failure
  Cytomegalovirus infection
  Hepatocellular carcinoma
  Huntington disease
  Inflammatory bowel disease
  Osteoarthritis
  Progressive multifocal leukoencephalopathy
  Promyelocytic leukaemia
  Stroke
  Basal cell nevus syndrome
  Bloom syndrome
  Rheumatoid arthritis
  Amyotrophic lateral sclerosis
  Kaposi sarcoma
  Lymphoma
  Nervous system inflammation
• UniProt ID: SUMO3_HUMAN
• PDB ID: 1U4A; 2IO1; 2MP2; 6K5R; 6NNQ; 7R2E; 7ZJU
• Pfam ID: PF11976
• Sequence:
  MSEEKPKEGVKTENDHINLKVAGQDGSVVQFKIKRHTPLSKLMKAYCERQGLSMRQIRFR
  FDGQPINETDTPAQLEMEDEDTIDVFQQQTGGVPESSLAGHSF
• Function: Ubiquitin-like protein which can be covalently attached to target lysines either as a monomer or as a lysine-linked polymer. Does not seem to be involved in protein degradation and may function as an antagonist of ubiquitin in the degradation process. Plays a role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Covalent attachment to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by an E3 ligase such as PIAS1-4, RANBP2 or CBX4. Plays a role in the regulation of sumoylation status of SETX.
• Tissue Specificity: Expressed predominantly in liver.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  SUMO is transferred from E1 to E2 (UBE2I, UBC9) (R-HSA-3065678)
  SUMO is proteolytically processed (R-HSA-3065679)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of transcription factors (R-HSA-3232118)
  SUMOylation of transcription cofactors (R-HSA-3899300)
  SUMOylation of intracellular receptors (R-HSA-4090294)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of DNA replication proteins (R-HSA-4615885)
  SUMOylation of immune response proteins (R-HSA-4755510)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  SUMO is conjugated to E1 (UBA2 (R-HSA-3065676)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Biomarker	[1]
Liver cancer	DISDE4BI	Definitive	Biomarker	[1]
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Biomarker	[2]
Bacillary dysentery	DISFZHKN	Strong	Biomarker	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[4]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Cytomegalovirus infection	DISCEMGC	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Huntington disease	DISQPLA4	Strong	Biomarker	[8]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[9]
Osteoarthritis	DIS05URM	Strong	Biomarker	[10]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[11]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[12]
Stroke	DISX6UHX	Strong	Biomarker	[5]
Basal cell nevus syndrome	DIST8BC2	moderate	Altered Expression	[13]
Bloom syndrome	DISKXQ7J	moderate	Genetic Variation	[14]
Rheumatoid arthritis	DISTSB4J	moderate	Altered Expression	[15]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[16]
Kaposi sarcoma	DISC1H1Z	Limited	Biomarker	[17]
Lymphoma	DISN6V4S	Limited	Biomarker	[18]
Nervous system inflammation	DISB3X5A	Limited	Genetic Variation	[19]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Small ubiquitin-related modifier 3 (SUMO3) affects the response to substance of Acetaminophen.	[29]

3 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 Small ubiquitin-related modifier 3 (SUMO3).	[20]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Small ubiquitin-related modifier 3 (SUMO3).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Small ubiquitin-related modifier 3 (SUMO3).	[26]

7 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 Small ubiquitin-related modifier 3 (SUMO3).	[21]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Small ubiquitin-related modifier 3 (SUMO3).	[23]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Small ubiquitin-related modifier 3 (SUMO3).	[24]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Small ubiquitin-related modifier 3 (SUMO3).	[24]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 decreases the expression of Small ubiquitin-related modifier 3 (SUMO3).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Small ubiquitin-related modifier 3 (SUMO3).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Small ubiquitin-related modifier 3 (SUMO3).	[28]

References

• [1] SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer.EBioMedicine. 2019 Feb;40:406-421. doi: 10.1016/j.ebiom.2018.12.031. Epub 2018 Dec 26.
• [2] A 15q24 microdeletion in transient myeloproliferative disease (TMD) and acute megakaryoblastic leukaemia (AMKL) implicates PML and SUMO3 in the leukaemogenesis of TMD/AMKL.Br J Haematol. 2012 Apr;157(2):180-7. doi: 10.1111/j.1365-2141.2012.09028.x. Epub 2012 Feb 1.
• [3] Sumoylation controls host anti-bacterial response to the gut invasive pathogen Shigella flexneri.EMBO Rep. 2014 Sep;15(9):965-72. doi: 10.15252/embr.201338386. Epub 2014 Aug 5.
• [4] Involvement of activated SUMO-2 conjugation in cardiomyopathy.Biochim Biophys Acta. 2015 Jul;1852(7):1388-99. doi: 10.1016/j.bbadis.2015.03.013. Epub 2015 Apr 6.
• [5] Hypothermia exerts early neuroprotective effects involving protein conjugation of SUMO?/3 in a rat model of middle cerebral artery occlusion.Mol Med Rep. 2017 Sep;16(3):3217-3223. doi: 10.3892/mmr.2017.6994. Epub 2017 Jul 15.
• [6] Small ubiquitin-related modifier (SUMO) pathway-mediated enhancement of human cytomegalovirus replication correlates with a recruitment of SUMO-1/3 proteins to viral replication compartments.J Gen Virol. 2013 Jun;94(Pt 6):1373-1384. doi: 10.1099/vir.0.051078-0. Epub 2013 Feb 13.
• [7] Small ubiquitin-related modifier 2/3 interacts with p65 and stabilizes it in the cytoplasm in HBV-associated hepatocellular carcinoma.BMC Cancer. 2015 Oct 12;15:675. doi: 10.1186/s12885-015-1665-3.
• [8] SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation.Cell Rep. 2013 Jul 25;4(2):362-75. doi: 10.1016/j.celrep.2013.06.034. Epub 2013 Jul 18.
• [9] A nanogel based oral gene delivery system targeting SUMOylation machinery to combat gut inflammation.Nanoscale. 2019 Mar 14;11(11):4970-4986. doi: 10.1039/c8nr09599j.
• [10] Regulation of matrixmetalloproteinase-3 and matrixmetalloproteinase-13 by SUMO-2/3 through the transcription factor NF-B.Ann Rheum Dis. 2013 Nov;72(11):1874-81. doi: 10.1136/annrheumdis-2012-202080. Epub 2013 Feb 16.
• [11] SUMOylation promotes PML degradation during encephalomyocarditis virus infection.J Virol. 2010 Nov;84(22):11634-45. doi: 10.1128/JVI.01321-10. Epub 2010 Sep 8.
• [12] Kaposi's sarcoma-associated herpesvirus K-Rta exhibits SUMO-targeting ubiquitin ligase (STUbL) like activity and is essential for viral reactivation.PLoS Pathog. 2013;9(8):e1003506. doi: 10.1371/journal.ppat.1003506. Epub 2013 Aug 22.
• [13] Down-regulation of SMT3A gene expression in association with DNA synthesis induction after X-ray irradiation in nevoid basal cell carcinoma syndrome (NBCCS) cells.Mutat Res. 2005 Oct 15;578(1-2):327-32. doi: 10.1016/j.mrfmmm.2005.06.027.
• [14] Small ubiquitin-related modifier (SUMO) binding determines substrate recognition and paralog-selective SUMO modification.J Biol Chem. 2008 Oct 24;283(43):29405-15. doi: 10.1074/jbc.M803632200. Epub 2008 Aug 15.
• [15] Role of small ubiquitin-like modifier proteins-1 (SUMO-1) in regulating migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis.Exp Cell Res. 2019 Feb 1;375(1):52-61. doi: 10.1016/j.yexcr.2018.12.011. Epub 2018 Dec 15.
• [16] SUMO3 modification accelerates the aggregation of ALS-linked SOD1 mutants.PLoS One. 2014 Jun 27;9(6):e101080. doi: 10.1371/journal.pone.0101080. eCollection 2014.
• [17] SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication.PLoS Pathog. 2017 Feb 17;13(2):e1006216. doi: 10.1371/journal.ppat.1006216. eCollection 2017 Feb.
• [18] Epstein-Barr Virus Latent Membrane Protein-1 Induces the Expression of SUMO-1 and SUMO-2/3 in LMP1-positive Lymphomas and Cells.Sci Rep. 2019 Jan 18;9(1):208. doi: 10.1038/s41598-018-36312-4.
• [19] Sumoylation of RORt regulates T(H)17 differentiation and thymocyte development.Nat Commun. 2018 Nov 19;9(1):4870. doi: 10.1038/s41467-018-07203-z.
• [20] 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.
• [21] 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.
• [22] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [23] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [24] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [25] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [26] 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.
• [27] Effect of endosulfan and bisphenol A on the expression of SUMO and UBC9. Drug Chem Toxicol. 2020 Nov;43(6):637-644. doi: 10.1080/01480545.2018.1526179. Epub 2018 Nov 14.
• [28] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [29] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.