Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW8Q5TF)

• DOT Name: E3 ubiquitin-protein ligase TRAF7 (TRAF7)
• Synonyms: EC 2.3.2.-; EC 2.3.2.27; RING finger and WD repeat-containing protein 1; RING finger protein 119; RING-type E3 ubiquitin transferase TRAF7; TNF receptor-associated factor 7
• Gene Name: TRAF7
• Related Disease:
  Cardiac, facial, and digital anomalies with developmental delay
  Mesothelioma
  Acute myelogenous leukaemia
  Hepatocellular carcinoma
  Meningioma
  Malignant mesothelioma
  Peritoneal mesothelioma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
• UniProt ID: TRAF7_HUMAN
• EC Number: 2.3.2.-; 2.3.2.27
• Pfam ID: PF00400 ; PF13445
• Sequence:
  MSSGKSARYNRFSGGPSNLPTPDVTTGTRMETTFGPAFSAVTTITKADGTSTYKQHCRTP
  SSSSTLAYSPRDEEDSMPPISTPRRSDSAISVRSLHSESSMSLRSTFSLPEEEEEPEPLV
  FAEQPSVKLCCQLCCSVFKDPVITTCGHTFCRRCALKSEKCPVDNVKLTVVVNNIAVAEQ
  IGELFIHCRHGCRVAGSGKPPIFEVDPRGCPFTIKLSARKDHEGSCDYRPVRCPNNPSCP
  PLLRMNLEAHLKECEHIKCPHSKYGCTFIGNQDTYETHLETCRFEGLKEFLQQTDDRFHE
  MHVALAQKDQEIAFLRSMLGKLSEKIDQLEKSLELKFDVLDENQSKLSEDLMEFRRDASM
  LNDELSHINARLNMGILGSYDPQQIFKCKGTFVGHQGPVWCLCVYSMGDLLFSGSSDKTI
  KVWDTCTTYKCQKTLEGHDGIVLALCIQGCKLYSGSADCTIIVWDIQNLQKVNTIRAHDN
  PVCTLVSSHNVLFSGSLKAIKVWDIVGTELKLKKELTGLNHWVRALVAAQSYLYSGSYQT
  IKIWDIRTLDCIHVLQTSGGSVYSIAVTNHHIVCGTYENLIHVWDIESKEQVRTLTGHVG
  TVYALAVISTPDQTKVFSASYDRSLRVWSMDNMICTQTLLRHQGSVTALAVSRGRLFSGA
  VDSTVKVWTC
• Function: E3 ubiquitin and SUMO-protein ligase that plays a role in different biological processes such as innate immunity, inflammation or apoptosis. Potentiates MAP3K3-mediated activation of JUN/AP1 and DDIT3 transcriptional regulators. Negatively regulates MYB transcriptional activity by sequestering it to the cytosol via SUMOylation. Plays a role in the phosphorylation of MAPK1 and/or MAPK3, probably via its interaction with MAP3K3. Negatively regulates RLR-mediated innate immunity by promoting 'Lys-48'-linked ubiquitination of TBK1 through its RING domain to inhibit the cellular antiviral response. Promotes 'Lys-29'-linked polyubiquitination of NEMO/IKBKG and RELA leading to targeting these two proteins to lysosomal degradative pathways, reducing the transcriptional activity of NF-kappa-B.
• Tissue Specificity: Ubiquitously expressed with high levels in skeletal muscle, heart, colon, spleen, kidney, liver and placenta.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac, facial, and digital anomalies with developmental delay	DISOOR79	Definitive	Autosomal dominant	[1]
Mesothelioma	DISKWK9M	Definitive	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Meningioma	DISPT4TG	Strong	Genetic Variation	[5]
Malignant mesothelioma	DISTHJGH	moderate	Genetic Variation	[6]
Peritoneal mesothelioma	DISW7W4V	Disputed	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Limited	Biomarker	[7]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[7]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[7]

4 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 E3 ubiquitin-protein ligase TRAF7 (TRAF7).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of E3 ubiquitin-protein ligase TRAF7 (TRAF7).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of E3 ubiquitin-protein ligase TRAF7 (TRAF7).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of E3 ubiquitin-protein ligase TRAF7 (TRAF7).	[12]

2 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 TRAF7 (TRAF7).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of E3 ubiquitin-protein ligase TRAF7 (TRAF7).	[13]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Molecular characterization of localized pleural mesothelioma.Mod Pathol. 2020 Feb;33(2):271-280. doi: 10.1038/s41379-019-0330-9. Epub 2019 Aug 1.
• [3] MicroRNA-126 attenuates cell apoptosis by targeting TRAF7 in acute myeloid leukemia cells.Biochem Cell Biol. 2018 Dec;96(6):840-846. doi: 10.1139/bcb-2018-0017.
• [4] TRAF7 enhances ubiquitin-degradation of KLF4 to promote hepatocellular carcinoma progression.Cancer Lett. 2020 Jan 28;469:380-389. doi: 10.1016/j.canlet.2019.11.012. Epub 2019 Nov 12.
• [5] Non-NF2 mutations have a key effect on inhibitory immune checkpoints and tumor pathogenesis in skull base meningiomas.J Neurooncol. 2019 Aug;144(1):11-20. doi: 10.1007/s11060-019-03198-9. Epub 2019 Jun 8.
• [6] Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42.Mod Pathol. 2019 Jan;32(1):88-99. doi: 10.1038/s41379-018-0127-2. Epub 2018 Aug 31.
• [7] Downregulation of ubiquitin E3 ligase TNF receptor-associated factor 7 leads to stabilization of p53 in breast cancer.Oncol Rep. 2013 Jan;29(1):283-7. doi: 10.3892/or.2012.2121. Epub 2012 Nov 1.
• [8] 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.
• [9] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.