Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBSMX0B)

• DOT Name: Tripartite motif-containing protein 6 (TRIM6)
• Synonyms: EC 2.3.2.27; RING finger protein 89; RING-type E3 ubiquitin transferase TRIM6
• Gene Name: TRIM6
• Related Disease:
  Acute myelogenous leukaemia
  Ebola virus infection
  Viral hemorrhagic fever
• UniProt ID: TRIM6_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF00622 ; PF00643 ; PF13445
• Sequence:
  MTSPVLVDIREEVTCPICLELLTEPLSIDCGHSFCQACITPNGRESVIGQEGERSCPVCQ
  TSYQPGNLRPNRHLANIVRRLREVVLGPGKQLKAVLCADHGEKLQLFCQEDGKVICWLCE
  RSQEHRGHHTFLVEEVAQEYQEKFQESLKKLKNEEQEAEKLTAFIREKKTSWKNQMEPER
  CRIQTEFNQLRNILDRVEQRELKKLEQEEKKGLRIIEEAENDLVHQTQSLRELISDLERR
  CQGSTMELLQDVSDVTERSEFWTLRKPEALPTKLRSMFRAPDLKRMLRVCRELTDVQSYW
  VDVTLNPHTANLNLVLAKNRRQVRFVGAKVSGPSCLEKHYDCSVLGSQHFSSGKHYWEVD
  VAKKTAWILGVCSNSLGPTFSFNHFAQNHSAYSRYQPQSGYWVIGLQHNHEYRAYEDSSP
  SLLLSMTVPPRRVGVFLDYEAGTVSFYNVTNHGFPIYTFSKYYFPTTLCPYFNPCNCVIP
  MTLRRPSS
• Function: E3 ubiquitin ligase that plays a crucial role in the activation of the IKBKE-dependent branch of the type I interferon signaling pathway. In concert with the ubiquitin-conjugating E2 enzyme UBE2K, synthesizes unanchored 'Lys-48'-linked polyubiquitin chains that promote the oligomerization and autophosphorylation of IKBKE leading to stimulation of an antiviral response. Ubiquitinates also MYC and inhibits its transcription activation activity, maintaining the pluripotency of embryonic stem cells. Promotes the association of unanchored 'Lys-48'-polyubiquitin chains with DHX16 leading to enhanced RIGI-mediated innate antiviral immune response ; (Microbial infection) Ubiquitinates ebolavirus protein VP35 leading to enhanced viral transcriptase activity.
• Reactome Pathway: Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[1]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[2]
Viral hemorrhagic fever	DISQEBTU	Limited	Biomarker	[2]

11 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 Tripartite motif-containing protein 6 (TRIM6).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tripartite motif-containing protein 6 (TRIM6).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tripartite motif-containing protein 6 (TRIM6).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Tripartite motif-containing protein 6 (TRIM6).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Tripartite motif-containing protein 6 (TRIM6).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Tripartite motif-containing protein 6 (TRIM6).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Tripartite motif-containing protein 6 (TRIM6).	[10]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Tripartite motif-containing protein 6 (TRIM6).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tripartite motif-containing protein 6 (TRIM6).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tripartite motif-containing protein 6 (TRIM6).	[13]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Tripartite motif-containing protein 6 (TRIM6).	[14]

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 Tripartite motif-containing protein 6 (TRIM6).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tripartite motif-containing protein 6 (TRIM6).	[12]

References

• [1] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [2] The Host E3-Ubiquitin Ligase TRIM6 Ubiquitinates the Ebola Virus VP35 Protein and Promotes Virus Replication.J Virol. 2017 Aug 24;91(18):e00833-17. doi: 10.1128/JVI.00833-17. Print 2017 Sep 15.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [6] 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.
• [7] 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.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [12] 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.
• [13] 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.
• [14] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.