Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTESLVP9)

• DOT Name: E3 ubiquitin-protein ligase TRIM39 (TRIM39)
• Synonyms: EC 2.3.2.27; RING finger protein 23; RING-type E3 ubiquitin transferase TRIM39; Testis-abundant finger protein; Tripartite motif-containing protein 39
• Gene Name: TRIM39
• Related Disease:
  Barrett esophagus
  Behcet disease
  Inflammatory bowel disease
  Leukoencephalopathy with vanishing white matter
  Mitochondrial trifunctional protein deficiency
  Rheumatoid arthritis
  Cutaneous lupus erythematosus
• UniProt ID: TRI39_HUMAN
• PDB ID: 2DID; 2DIF; 2ECJ
• EC Number: 2.3.2.27
• Pfam ID: PF13765 ; PF00622 ; PF00643 ; PF15227
• Sequence:
  MAETSLLEAGASAASTAAALENLQVEASCSVCLEYLKEPVIIECGHNFCKACITRWWEDL
  ERDFPCPVCRKTSRYRSLRPNRQLGSMVEIAKQLQAVKRKIRDESLCPQHHEALSLFCYE
  DQEAVCLICAISHTHRAHTVVPLDDATQEYKEKLQKCLEPLEQKLQEITRCKSSEEKKPG
  ELKRLVESRRQQILREFEELHRRLDEEQQVLLSRLEEEEQDILQRLRENAAHLGDKRRDL
  AHLAAEVEGKCLQSGFEMLKDVKSTLEKNIPRKFGGSLSTICPRDHKALLGLVKEINRCE
  KVKTMEVTSVSIELEKNFSNFPRQYFALRKILKQLIADVTLDPETAHPNLVLSEDRKSVK
  FVETRLRDLPDTPRRFTFYPCVLATEGFTSGRHYWEVEVGDKTHWAVGVCRDSVSRKGEL
  TPLPETGYWRVRLWNGDKYAATTTPFTPLHIKVKPKRVGIFLDYEAGTLSFYNVTDRSHI
  YTFTDTFTEKLWPLFYPGIRAGRKNAAPLTIRPPTDWE
• Function: [Isoform 1]: E3 ubiquitin-protein ligase. May facilitate apoptosis by inhibiting APC/C-Cdh1-mediated poly-ubiquitination and subsequent proteasome-mediated degradation of the pro-apoptotic protein MOAP1. Regulates the G1/S transition of the cell cycle and DNA damage-induced G2 arrest by stabilizing CDKN1A/p21. Positively regulates CDKN1A/p21 stability by competing with DTL for CDKN1A/p21 binding, therefore disrupting DCX(DTL) E3 ubiquitin ligase complex-mediated CDKN1A/p21 ubiquitination and degradation ; [Isoform 2]: Regulates the G1/S transition of the cell cycle and DNA damage-induced G2 arrest by stabilizing CDKN1A/p21. Positively regulates CDKN1A/p21 stability by competing with DTL for CDKN1A/p21 binding, therefore disrupting DCX(DTL) E3 ubiquitin ligase complex-mediated CDKN1A/p21 ubiquitination and degradation. Negatively regulates the canonical NF-kappa-B signaling pathway via stabilization of CACTIN in an ubiquitination-independent manner.
• Tissue Specificity: Ubiquitous; highly expressed in brain, heart, kidney, liver, skeletal muscle, spleen and testis.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Barrett esophagus	DIS416Y7	Strong	Biomarker	[1]
Behcet disease	DISSYMBS	Strong	Biomarker	[2]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[3]
Leukoencephalopathy with vanishing white matter	DIS3J8NN	Strong	Biomarker	[1]
Mitochondrial trifunctional protein deficiency	DIS2MYYR	Strong	Genetic Variation	[4]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[5]
Cutaneous lupus erythematosus	DISOIX6L	moderate	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of E3 ubiquitin-protein ligase TRIM39 (TRIM39).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase TRIM39 (TRIM39).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase TRIM39 (TRIM39).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase TRIM39 (TRIM39).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase TRIM39 (TRIM39).	[10]

References

• [1] Genome-wide association study identifies new susceptibility loci for cutaneous lupus erythematosus.Exp Dermatol. 2015 Jul;24(7):510-5. doi: 10.1111/exd.12708. Epub 2015 May 4.
• [2] TRIM39 and RNF39 are associated with Behet's disease independently of HLA-B?1 and -A?6.Biochem Biophys Res Commun. 2010 Oct 29;401(4):533-7. doi: 10.1016/j.bbrc.2010.09.088. Epub 2010 Sep 27.
• [3] DNA Methylation Profiling in Inflammatory Bowel Disease Provides New Insights into Disease Pathogenesis.J Crohns Colitis. 2016 Jan;10(1):77-86. doi: 10.1093/ecco-jcc/jjv176. Epub 2015 Sep 28.
• [4] A diagnostic algorithm for metabolic myopathies.Curr Neurol Neurosci Rep. 2010 Mar;10(2):118-26. doi: 10.1007/s11910-010-0096-4.
• [5] REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.Nat Genet. 2009 Jul;41(7):820-3. doi: 10.1038/ng.395. Epub 2009 Jun 7.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] 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.