Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS0DJIP)

• DOT Name: Tripartite motif-containing protein 26 (TRIM26)
• Synonyms: EC 2.3.2.27; Acid finger protein; AFP; RING finger protein 95; Zinc finger protein 173
• Gene Name: TRIM26
• Related Disease:
  Advanced cancer
  Asthma
  Attention deficit hyperactivity disorder
  Bipolar disorder
  Hepatocellular carcinoma
  Major depressive disorder
  Respiratory disease
  Rheumatoid arthritis
  Schizophrenia
  Thyroid gland papillary carcinoma
  Vitiligo
  Neoplasm
  Lung carcinoma
  Lung squamous cell carcinoma
  Nasopharyngeal carcinoma
• UniProt ID: TRI26_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13765 ; PF00622 ; PF00643 ; PF15227
• Sequence:
  MATSAPLRSLEEEVTCSICLDYLRDPVTIDCGHVFCRSCTTDVRPISGSRPVCPLCKKPF
  KKENIRPVWQLASLVENIERLKVDKGRQPGEVTREQQDAKLCERHREKLHYYCEDDGKLL
  CVMCRESREHRPHTAVLMEKAAQPHREKILNHLSTLRRDRDKIQGFQAKGEADILAALKK
  LQDQRQYIVAEFEQGHQFLREREEHLLEQLAKLEQELTEGREKFKSRGVGELARLALVIS
  ELEGKAQQPAAELMQDTRDFLNRYPRKKFWVGKPIARVVKKKTGEFSDKLLSLQRGLREF
  QGKLLRDLEYKTVSVTLDPQSASGYLQLSEDWKCVTYTSLYKSAYLHPQQFDCEPGVLGS
  KGFTWGKVYWEVEVEREGWSEDEEEGDEEEEGEEEEEEEEAGYGDGYDDWETDEDEESLG
  DEEEEEEEEEEEVLESCMVGVARDSVKRKGDLSLRPEDGVWALRLSSSGIWANTSPEAEL
  FPALRPRRVGIALDYEGGTVTFTNAESQELIYTFTATFTRRLVPFLWLKWPGTRLLLRP
• Function: E3 ubiquitin-protein ligase which regulates the IFN-beta production and antiviral response downstream of various DNA-encoded pattern-recognition receptors (PRRs). Plays also a central role in determining the response to different forms of oxidative stress by controlling levels of DNA glycosylases NEIL1, NEIL3 and NTH1 that are involved in repair of damaged DNA. Promotes nuclear IRF3 ubiquitination and proteasomal degradation. Bridges together TBK1 and NEMO during the innate response to viral infection leading to the activation of TBK1. Positively regulates LPS-mediated inflammatory innate immune response by catalyzing the 'Lys-11'-linked polyubiquitination of TAB1 to enhance its activation and subsequent NF-kappa-B and MAPK signaling. In a manner independent of its catalytic activity, inhibits WWP2, a SOX2-directed E3 ubiquitin ligase, and thus protects SOX2 from polyubiquitination and proteasomal degradation. Ubiquitinates the histone acetyltransferase protein complex component PHF20 and thereby triggers its degradation in the nucleus after its recruitment by the histone demethylase KDM6B, serving as a scaffold protein. Upon induction by TGF-beta, ubiquitinates the TFIID component TAF7 for proteasomal degradation. Induces ferroptosis by ubiquitinating SLC7A11, a critical protein for lipid reactive oxygen species (ROS) scavenging. Inhibits directly hepatitis B virus replication by mediating HBX ubiquitination and subsequent degradation ; (Microbial infection) Promotes herpes simplex virus type 2/HHV-2 infection in vaginal epithelial cells by decreasing the nuclear localization of IRF3, the primary mediator of type I interferon activation.
• Reactome Pathway: Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Asthma	DISW9QNS	Strong	Genetic Variation	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[3]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[3]
Respiratory disease	DISGGAGJ	Strong	Genetic Variation	[2]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[4]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[5]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[6]
Vitiligo	DISR05SL	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	moderate	Biomarker	[6]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[8]
Lung squamous cell carcinoma	DISXPIBD	Limited	Genetic Variation	[8]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[9]

15 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 26 (TRIM26).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tripartite motif-containing protein 26 (TRIM26).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tripartite motif-containing protein 26 (TRIM26).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tripartite motif-containing protein 26 (TRIM26).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tripartite motif-containing protein 26 (TRIM26).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tripartite motif-containing protein 26 (TRIM26).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Tripartite motif-containing protein 26 (TRIM26).	[17]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Tripartite motif-containing protein 26 (TRIM26).	[18]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Tripartite motif-containing protein 26 (TRIM26).	[13]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Tripartite motif-containing protein 26 (TRIM26).	[13]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Tripartite motif-containing protein 26 (TRIM26).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tripartite motif-containing protein 26 (TRIM26).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tripartite motif-containing protein 26 (TRIM26).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tripartite motif-containing protein 26 (TRIM26).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Tripartite motif-containing protein 26 (TRIM26).	[23]

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 26 (TRIM26).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tripartite motif-containing protein 26 (TRIM26).	[20]

References

• [1] TRIM26 functions as a novel tumor suppressor of hepatocellular carcinoma and its downregulation contributes to worse prognosis.Biochem Biophys Res Commun. 2015 Jul 31;463(3):458-65. doi: 10.1016/j.bbrc.2015.05.117. Epub 2015 Jun 1.
• [2] Association study between TRIM26 polymorphisms and risk of aspirin-exacerbated respiratory disease.Int J Mol Med. 2012 May;29(5):927-33. doi: 10.3892/ijmm.2012.898. Epub 2012 Jan 26.
• [3] Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.Lancet. 2013 Apr 20;381(9875):1371-1379. doi: 10.1016/S0140-6736(12)62129-1. Epub 2013 Feb 28.
• [4] 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.
• [5] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [6] Overexpression of TRIM26 suppresses the proliferation, metastasis, and glycolysis in papillary thyroid carcinoma cells.J Cell Physiol. 2019 Aug;234(10):19019-19027. doi: 10.1002/jcp.28541. Epub 2019 Mar 29.
• [7] Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC.Nat Genet. 2010 Jul;42(7):614-8. doi: 10.1038/ng.603. Epub 2010 Jun 6.
• [8] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [9] A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response.Cancer Med. 2018 Aug;7(8):3848-3861. doi: 10.1002/cam4.1537. Epub 2018 Jun 28.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [14] 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.
• [15] 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.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [18] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] 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.
• [22] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.