Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPU0CO4)

• DOT Name: E3 ubiquitin-protein ligase RNF138 (RNF138)
• Synonyms: EC 2.3.2.27; Nemo-like kinase-associated RING finger protein; NLK-associated RING finger protein; hNARF; RING finger protein 138; RING-type E3 ubiquitin transferase RNF138
• Gene Name: RNF138
• Related Disease:
  Crohn disease
  Adult glioblastoma
  Astrocytoma
  Cerebellar ataxia
  Episodic ataxia type 2
  Glioma
  Neoplasm
  Pathologic nystagmus
  Gastric cancer
  Glioblastoma multiforme
  Stomach cancer
• UniProt ID: RN138_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13923 ; PF05605 ; PF18574
• Sequence:
  MAEDLSAATSYTEDDFYCPVCQEVLKTPVRTTACQHVFCRKCFLTAMRESGAHCPLCRGN
  VTRRERACPERALDLENIMRKFSGSCRCCAKQIKFYRMRHHYKSCKKYQDEYGVSSIIPN
  FQISQDSVGNSNRSETSTSDNTETYQENTSSSGHPTFKCPLCQESNFTRQRLLDHCNSNH
  LFQIVPVTCPICVSLPWGDPSQITRNFVSHLNQRHQFDYGEFVNLQLDEETQYQTAVEES
  FQVNI
• Function: E3 ubiquitin-protein ligase involved in DNA damage response by promoting DNA resection and homologous recombination. Recruited to sites of double-strand breaks following DNA damage and specifically promotes double-strand break repair via homologous recombination. Two different, non-exclusive, mechanisms have been proposed. According to a report, regulates the choice of double-strand break repair by favoring homologous recombination over non-homologous end joining (NHEJ): acts by mediating ubiquitination of XRCC5/Ku80, leading to remove the Ku complex from DNA breaks, thereby promoting homologous recombination. According to another report, cooperates with UBE2Ds E2 ubiquitin ligases (UBE2D1, UBE2D2, UBE2D3 or UBE2D4) to promote homologous recombination by mediating ubiquitination of RBBP8/CtIP. Together with NLK, involved in the ubiquitination and degradation of TCF/LEF. Also exhibits auto-ubiquitination activity in combination with UBE2K. May act as a negative regulator in the Wnt/beta-catenin-mediated signaling pathway.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Astrocytoma	DISL3V18	Strong	Altered Expression	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Altered Expression	[4]
Episodic ataxia type 2	DISQ76GV	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Pathologic nystagmus	DIS1QSPO	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Limited	Biomarker	[6]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[2]
Stomach cancer	DISKIJSX	Limited	Biomarker	[6]

8 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 RNF138 (RNF138).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase RNF138 (RNF138).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E3 ubiquitin-protein ligase RNF138 (RNF138).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of E3 ubiquitin-protein ligase RNF138 (RNF138).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of E3 ubiquitin-protein ligase RNF138 (RNF138).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of E3 ubiquitin-protein ligase RNF138 (RNF138).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of E3 ubiquitin-protein ligase RNF138 (RNF138).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase RNF138 (RNF138).	[13]

References

• [1] Influence of smoking on colonic gene expression profile in Crohn's disease.PLoS One. 2009 Jul 15;4(7):e6210. doi: 10.1371/journal.pone.0006210.
• [2] RNF138-mediated ubiquitination of rpS3 is required for resistance of glioblastoma cells to radiation-induced apoptosis.Exp Mol Med. 2018 Jan 26;50(1):e434. doi: 10.1038/emm.2017.247.
• [3] A novel gene RNF138 expressed in human gliomas and its function in the glioma cell line U251.Anal Cell Pathol (Amst). 2012;35(3):167-78. doi: 10.3233/ACP-2011-0051.
• [4] Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Ca(v)2.1 (P/Q-Type) Calcium Channels.J Neurosci. 2017 Mar 1;37(9):2485-2503. doi: 10.1523/JNEUROSCI.3070-16.2017. Epub 2017 Feb 6.
• [5] Downregulation of RNF138 inhibits cellular proliferation, migration, invasion and EMT in glioma cells via suppression of the Erk signaling pathway.Oncol Rep. 2018 Dec;40(6):3285-3296. doi: 10.3892/or.2018.6744. Epub 2018 Sep 28.
• [6] RNF138 confers cisplatin resistance in gastric cancer cells via activating Chk1 signaling pathway.Cancer Biol Ther. 2018;19(12):1128-1138. doi: 10.1080/15384047.2018.1480293. Epub 2018 Sep 27.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] 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.