Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEO4UCZ)

• DOT Name: Tripartite motif-containing protein 10 (TRIM10)
• Synonyms: B30-RING finger protein; RING finger protein 9
• Gene Name: TRIM10
• Related Disease:
  Irritant contact dermatitis
  Parkinson disease
  Rheumatoid arthritis
  Schizophrenia
  Lung cancer
• UniProt ID: TRI10_HUMAN
• PDB ID: 7QS0
• Pfam ID: PF13765 ; PF00622 ; PF00643 ; PF00097
• Sequence:
  MASAASVTSLADEVNCPICQGTLREPVTIDCGHNFCRACLTRYCEIPGPDLEESPTCPLC
  KEPFRPGSFRPNWQLANVVENIERLQLVSTLGLGEEDVCQEHGEKIYFFCEDDEMQLCVV
  CREAGEHATHTMRFLEDAAAPYREQIHKCLKCLRKEREEIQEIQSRENKRMQVLLTQVST
  KRQQVISEFAHLRKFLEEQQSILLAQLESQDGDILRQRDEFDLLVAGEICRFSALIEELE
  EKNERPARELLTDIRSTLIRCETRKCRKPVAVSPELGQRIRDFPQQALPLQREMKMFLEK
  LCFELDYEPAHISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGI
  TGGRHTWVVSIDLAHGGSCTVGVVSEDVQRKGELRLRPEEGVWAVRLAWGFVSALGSFPT
  RLTLKEQPRQVRVSLDYEVGWVTFTNAVTREPIYTFTASFTRKVIPFFGLWGRGSSFSLS
  S
• Function: E3 ligase that plays an essential role in the differentiation and survival of terminal erythroid cells. May directly bind to PTEN and promote its ubiquitination, resulting in its proteasomal degradation and activation of hypertrophic signaling. In addition, plays a role in immune response regulation by repressing the phosphorylation of STAT1 and STAT2 in the interferon/JAK/STAT signaling pathway independent of its E3 ligase activity. Mechanistically, interacts with the intracellular domain of IFNAR1 and thereby inhibits the association between TYK2 and IFNAR1.
• Reactome Pathway: Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Irritant contact dermatitis	DIS62JY3	Strong	Biomarker	[1]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[2]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tripartite motif-containing protein 10 (TRIM10).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tripartite motif-containing protein 10 (TRIM10).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tripartite motif-containing protein 10 (TRIM10).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Tripartite motif-containing protein 10 (TRIM10).	[10]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Tripartite motif-containing protein 10 (TRIM10).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tripartite motif-containing protein 10 (TRIM10).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tripartite motif-containing protein 10 (TRIM10).	[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 10 (TRIM10).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Tripartite motif-containing protein 10 (TRIM10).	[11]

References

• [1] Association of MHC region SNPs with irritant susceptibility in healthcare workers. J Immunotoxicol. 2016 Sep;13(5):738-44. doi: 10.3109/1547691X.2016.1173135. Epub 2016 Jun 3.
• [2] Silencing of TRIM10 alleviates apoptosis in cellular model of Parkinson's disease.Biochem Biophys Res Commun. 2019 Oct 20;518(3):451-458. doi: 10.1016/j.bbrc.2019.08.041. Epub 2019 Aug 28.
• [3] 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.
• [4] Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
• [5] A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese.Nat Genet. 2011 Jul 3;43(8):792-6. doi: 10.1038/ng.875.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.