Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBD1Q3X)

• DOT Name: E3 ubiquitin-protein ligase RNF125 (RNF125)
• Synonyms: EC 2.3.2.27; RING finger protein 125; T-cell RING activation protein 1; TRAC-1
• Gene Name: RNF125
• Related Disease:
  Clear cell renal carcinoma
  Fatty liver disease
  Intellectual disability
  Overgrowth syndrome
  Renal cell carcinoma
  Sjogren syndrome
  Tenorio syndrome
  Melanoma
  Neoplasm
  Gallbladder cancer
  Gallbladder carcinoma
• UniProt ID: RN125_HUMAN
• PDB ID: 5DKA; 8GBQ; 8GCB
• EC Number: 2.3.2.27
• Pfam ID: PF13923 ; PF05605 ; PF18574
• Sequence:
  MGSVLSTDSGKSAPASATARALERRRDPELPVTSFDCAVCLEVLHQPVRTRCGHVFCRSC
  IATSLKNNKWTCPYCRAYLPSEGVPATDVAKRMKSEYKNCAECDTLVCLSEMRAHIRTCQ
  KYIDKYGPLQELEETAARCVCPFCQRELYEDSLLDHCITHHRSERRPVFCPLCRLIPDEN
  PSSFSGSLIRHLQVSHTLFYDDFIDFNIIEEALIRRVLDRSLLEYVNHSNTT
• Function: E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins, such as RIGI, MAVS/IPS1, IFIH1/MDA5, JAK1 and p53/TP53. Acts as a negative regulator of type I interferon production by mediating ubiquitination of RIGI at 'Lys-181', leading to RIGI degradation. Mediates ubiquitination and subsequent degradation of p53/TP53. Mediates ubiquitination and subsequent degradation of JAK1. Acts as a positive regulator of T-cell activation.
• Tissue Specificity: Predominantly expressed in lymphoid tissues, including bone marrow, spleen and thymus. Also weakly expressed in other tissues. Predominant in the CD4(+) and CD8(+) T-cells, suggesting that it is preferentially confined to T-cells.
• KEGG Pathway: RIG-I-like receptor sig.ling pathway (hsa04622)
• Reactome Pathway: Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[1]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[2]
Intellectual disability	DISMBNXP	Strong	Biomarker	[3]
Overgrowth syndrome	DISHK54G	Strong	Genetic Variation	[3]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[1]
Sjogren syndrome	DISUBX7H	Strong	Genetic Variation	[3]
Tenorio syndrome	DISWLZGY	Strong	Autosomal dominant	[4]
Melanoma	DIS1RRCY	moderate	Altered Expression	[5]
Neoplasm	DISZKGEW	moderate	Altered Expression	[5]
Gallbladder cancer	DISXJUAF	Limited	Altered Expression	[6]
Gallbladder carcinoma	DISD6ACL	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of E3 ubiquitin-protein ligase RNF125 (RNF125).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase RNF125 (RNF125).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase RNF125 (RNF125).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase RNF125 (RNF125).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of E3 ubiquitin-protein ligase RNF125 (RNF125).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of E3 ubiquitin-protein ligase RNF125 (RNF125).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of E3 ubiquitin-protein ligase RNF125 (RNF125).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase RNF125 (RNF125).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of E3 ubiquitin-protein ligase RNF125 (RNF125).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase RNF125 (RNF125).	[15]

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 E3 ubiquitin-protein ligase RNF125 (RNF125).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase RNF125 (RNF125).	[16]

References

• [1] Network spatio-temporal analysis predicts disease stage-related genes and pathways in renal cell carcinoma.Genet Mol Res. 2016 May 6;15(2). doi: 10.4238/gmr.15028061.
• [2] Association between hepatic steatosis and hepatic expression of genes involved in innate immunity in patients with chronic hepatitis C.Cytokine. 2013 Aug;63(2):145-50. doi: 10.1016/j.cyto.2013.04.012. Epub 2013 May 11.
• [3] A new overgrowth syndrome is due to mutations in RNF125. Hum Mutat. 2014 Dec;35(12):1436-41. doi: 10.1002/humu.22689.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation.Cell Rep. 2015 Jun 9;11(9):1458-73. doi: 10.1016/j.celrep.2015.04.049. Epub 2015 May 28.
• [6] Ring finger protein 125, as a potential highly aggressive and unfavorable prognostic biomarker, promotes the invasion and metastasis of human gallbladder cancers via activating the TGF- 1-SMAD3-ID1 signaling pathway.Oncotarget. 2017 Jul 25;8(30):49897-49914. doi: 10.18632/oncotarget.18180.
• [7] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [8] 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.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] 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.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [14] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [15] 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.
• [16] 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.