Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMPT9Y2)

• DOT Name: E3 ubiquitin-protein ligase TRAIP (TRAIP)
• Synonyms: EC 2.3.2.27; RING finger protein 206; TRAF-interacting protein
• Gene Name: TRAIP
• Related Disease:
  Crohn disease
  Hepatocellular carcinoma
  Microlissencephaly
  Neoplasm
  Ulcerative colitis
  Acute myelogenous leukaemia
  Advanced cancer
  Fanconi anemia complementation group Q
  Isolated congenital microcephaly
  Metastatic malignant neoplasm
  Myeloproliferative neoplasm
  Psoriasis
  Seckel syndrome 9
  Isolated growth hormone deficiency type IA
  Seckel syndrome
  Lung cancer
  Lung carcinoma
• UniProt ID: TRAIP_HUMAN
• PDB ID: 4ZTD
• EC Number: 2.3.2.27
• Pfam ID: PF13639
• Sequence:
  MPIRALCTICSDFFDHSRDVAAIHCGHTFHLQCLIQWFETAPSRTCPQCRIQVGKRTIIN
  KLFFDLAQEEENVLDAEFLKNELDNVRAQLSQKDKEKRDSQVIIDTLRDTLEERNATVVS
  LQQALGKAEMLCSTLKKQMKYLEQQQDETKQAQEEARRLRSKMKTMEQIELLLQSQRPEV
  EEMIRDMGVGQSAVEQLAVYCVSLKKEYENLKEARKASGEVADKLRKDLFSSRSKLQTVY
  SELDQAKLELKSAQKDLQSADKEIMSLKKKLTMLQETLNLPPVASETVDRLVLESPAPVE
  VNLKLRRPSFRDDIDLNATFDVDTPPARPSSSQHGYYEKLCLEKSHSPIQDVPKKICKGP
  RKESQLSLGGQSCAGEPDEELVGAFPIFVRNAILGQKQPKRPRSESSCSKDVVRTGFDGL
  GGRTKFIQPTDTVMIRPLPVKPKTKVKQRVRVKTVPSLFQAKLDTFLWS
• Function: E3 ubiquitin ligase required to protect genome stability in response to replication stress. Acts as a key regulator of interstrand cross-link repair, which takes place when both strands of duplex DNA are covalently tethered together, thereby blocking replication and transcription. Controls the choice between the two pathways of replication-coupled interstrand-cross-link repair by mediating ubiquitination of MCM7 subunit of the CMG helicase complex. Short ubiquitin chains on MCM7 promote recruitment of DNA glycosylase NEIL3. If the interstrand cross-link cannot be cleaved by NEIL3, the ubiquitin chains continue to grow on MCM7, promoting the unloading of the CMG helicase complex by the VCP/p97 ATPase, enabling the Fanconi anemia DNA repair pathway. Only catalyzes ubiquitination of MCM7 when forks converge. Also involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis: promotes ubiquitination of DPCs, leading to their degradation by the proteasome. Has also been proposed to play a role in promoting translesion synthesis by mediating the assembly of 'Lys-63'-linked poly-ubiquitin chains on the Y-family polymerase POLN in order to facilitate bypass of DNA lesions and preserve genomic integrity. The function in translesion synthesis is however controversial. Acts as a regulator of the spindle assembly checkpoint. Also acts as a negative regulator of innate immune signaling by inhibiting activation of NF-kappa-B mediated by TNF. Negatively regulates TLR3/4- and RIG-I-mediated IRF3 activation and subsequent IFNB1 production and cellular antiviral response by promoting 'Lys-48'-linked polyubiquitination of TNK1 leading to its proteasomal degradation.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Definitive	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[2]
Microlissencephaly	DISUCKNT	Definitive	Biomarker	[3]
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[4]
Ulcerative colitis	DIS8K27O	Definitive	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[6]
Fanconi anemia complementation group Q	DISHYVNK	Strong	Autosomal recessive	[3]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[6]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Biomarker	[3]
Psoriasis	DIS59VMN	Strong	Biomarker	[7]
Seckel syndrome 9	DIS68DCJ	Strong	Autosomal recessive	[3]
Isolated growth hormone deficiency type IA	DISLPIAM	moderate	Genetic Variation	[3]
Seckel syndrome	DISEVUBA	Supportive	Autosomal recessive	[3]
Lung cancer	DISCM4YA	Disputed	Biomarker	[8]
Lung carcinoma	DISTR26C	Disputed	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[15]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[16]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[23]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[24]

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 increases the methylation of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase TRAIP (TRAIP).	[21]

References

• [1] Two-stage candidate gene study of chromosome 3p demonstrates an association between nonsynonymous variants in the MST1R gene and Crohn's disease.Inflamm Bowel Dis. 2008 Apr;14(4):500-7. doi: 10.1002/ibd.20365.
• [2] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [3] TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism. Nat Genet. 2016 Jan;48(1):36-43. doi: 10.1038/ng.3451. Epub 2015 Nov 23.
• [4] Aptamer-derived peptides as potent inhibitors of the oncogenic RhoGEF Tgat.Chem Biol. 2009 Apr 24;16(4):391-400. doi: 10.1016/j.chembiol.2009.02.006.
• [5] Aurora A and NF-B Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA.Cancer Res. 2017 Jan 15;77(2):494-508. doi: 10.1158/0008-5472.CAN-16-1004. Epub 2016 Nov 10.
• [6] DCUN1D1 facilitates tumor metastasis by activating FAK signaling and up-regulates PD-L1 in non-small-cell lung cancer.Exp Cell Res. 2019 Jan 15;374(2):304-314. doi: 10.1016/j.yexcr.2018.12.001. Epub 2018 Dec 4.
• [7] Fumaric acid esters for psoriasis: a systematic review.Ir J Med Sci. 2017 Feb;186(1):161-177. doi: 10.1007/s11845-016-1470-2. Epub 2016 Jun 7.
• [8] TIFA Promotes Cell Survival and Migration in Lung Adenocarcinoma.Cell Physiol Biochem. 2018;47(5):2097-2108. doi: 10.1159/000491478. Epub 2018 Jul 5.
• [9] 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.
• [10] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [16] Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis. 2006 May;27(5):916-24. doi: 10.1093/carcin/bgi312. Epub 2005 Dec 16.
• [17] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [24] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.