Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE4CO7E)

• DOT Name: E3 ubiquitin-protein ligase RNF146 (RNF146)
• Synonyms: EC 2.3.2.27; Dactylidin; Iduna; RING finger protein 146; RING-type E3 ubiquitin transferase RNF146
• Gene Name: RNF146
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Cerebral infarction
  Cleidocranial dysplasia 1
  Colorectal carcinoma
  Colorectal neoplasm
  Epithelial ovarian cancer
  Lung cancer
  Lung carcinoma
  Nasopharyngeal carcinoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Parkinson disease
  Stroke
  Neoplasm
• UniProt ID: RN146_HUMAN
• PDB ID: 2D8T; 3V3L; 6CF6
• EC Number: 2.3.2.27
• Pfam ID: PF02825 ; PF13920
• Sequence:
  MMAGCGEIDHSINMLPTNRKANESCSNTAPSLTVPECAICLQTCVHPVSLPCKHVFCYLC
  VKGASWLGKRCALCRQEIPEDFLDKPTLLSPEELKAASRGNGEYAWYYEGRNGWWQYDER
  TSRELEDAFSKGKKNTEMLIAGFLYVADLENMVQYRRNEHGRRRKIKRDIIDIPKKGVAG
  LRLDCDANTVNLARESSADGADSVSAQSGASVQPLVSSVRPLTSVDGQLTSPATPSPDAS
  TSLEDSFAHLQLSGDNTAERSHRGEGEEDHESPSSGRVPAPDTSIEETESDASSDSEDVS
  AVVAQHSLTQQRLLVSNANQTVPDRSDRSGTDRSVAGGGTVSVSVRSRRPDGQCTVTEV
• Function: E3 ubiquitin-protein ligase that specifically binds poly-ADP-ribosylated (PARsylated) proteins and mediates their ubiquitination and subsequent degradation. May regulate many important biological processes, such as cell survival and DNA damage response. Acts as an activator of the Wnt signaling pathway by mediating the ubiquitination of PARsylated AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex. Acts in cooperation with tankyrase proteins (TNKS and TNKS2), which mediate PARsylation of target proteins AXIN1, AXIN2, BLZF1, CASC3, TNKS and TNKS2. Recognizes and binds tankyrase-dependent PARsylated proteins via its WWE domain and mediates their ubiquitination, leading to their degradation. Different ubiquitin linkage types have been observed: TNKS2 undergoes ubiquitination at 'Lys-48' and 'Lys-63', while AXIN1 is only ubiquitinated at 'Lys-48'. May regulate TNKS and TNKS2 subcellular location, preventing aggregation at a centrosomal location. Neuroprotective protein. Protects the brain against N-methyl-D-aspartate (NMDA) receptor-mediated glutamate excitotoxicity and ischemia, by interfering with PAR-induced cell death, called parthanatos. Prevents nuclear translocation of AIFM1 in a PAR-binding dependent manner. Does not affect PARP1 activation. Protects against cell death induced by DNA damaging agents, such as N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and rescues cells from G1 arrest. Promotes cell survival after gamma-irradiation. Facilitates DNA repair.
• Tissue Specificity: Ubiquitously expressed. Up-regulated in brains from patients with Alzheimer disease.
• Reactome Pathway:
  Degradation of AXIN (R-HSA-4641257)
  Ub-specific processing proteases (R-HSA-5689880)
  Regulation of PTEN stability and activity (R-HSA-8948751)
  TCF dependent signaling in response to WNT (R-HSA-201681)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[3]
Cleidocranial dysplasia 1	DIS2OHLA	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Altered Expression	[7]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[7]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[6]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[9]
Stroke	DISX6UHX	moderate	Biomarker	[10]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[11]

9 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 RNF146 (RNF146).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF146 (RNF146).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase RNF146 (RNF146).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase RNF146 (RNF146).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of E3 ubiquitin-protein ligase RNF146 (RNF146).	[16]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of E3 ubiquitin-protein ligase RNF146 (RNF146).	[18]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of E3 ubiquitin-protein ligase RNF146 (RNF146).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase RNF146 (RNF146).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E3 ubiquitin-protein ligase RNF146 (RNF146).	[21]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of E3 ubiquitin-protein ligase RNF146 (RNF146).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of E3 ubiquitin-protein ligase RNF146 (RNF146).	[22]

References

• [1] Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling.Nat Commun. 2019 Sep 25;10(1):4363. doi: 10.1038/s41467-019-12377-1.
• [2] The novel cytosolic RING finger protein dactylidin is up-regulated in brains of patients with Alzheimer's disease.Eur J Neurosci. 2005 Mar;21(5):1289-98. doi: 10.1111/j.1460-9568.2005.03977.x.
• [3] Neuroprotectin D1 upregulates Iduna expression and provides protection in cellular uncompensated oxidative stress and in experimental ischemic stroke.Cell Death Differ. 2017 Jun;24(6):1091-1099. doi: 10.1038/cdd.2017.55. Epub 2017 Apr 21.
• [4] Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism.J Clin Invest. 2017 Jun 30;127(7):2612-2625. doi: 10.1172/JCI92233. Epub 2017 Jun 5.
• [5] The E3 ubiquitin ligase RNF146 promotes colorectal cancer by activating the Wnt/-catenin pathway via ubiquitination of Axin1.Biochem Biophys Res Commun. 2018 Sep 5;503(2):991-997. doi: 10.1016/j.bbrc.2018.06.107. Epub 2018 Jun 25.
• [6] The RNF146 and ECHDC1 genes as candidates for inherited breast and ovarian cancer in Jewish Ashkenazi women.Fam Cancer. 2009;8(4):399-402. doi: 10.1007/s10689-009-9255-7. Epub 2009 Jun 11.
• [7] Overexpression of RNF146 in non-small cell lung cancer enhances proliferation and invasion of tumors through the Wnt/-catenin signaling pathway.PLoS One. 2014 Jan 14;9(1):e85377. doi: 10.1371/journal.pone.0085377. eCollection 2014.
• [8] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [9] Rhododendrin-Induced RNF146 Expression via Estrogen Receptor Activation is Cytoprotective Against 6-OHDA-Induced Oxidative Stress.Int J Mol Sci. 2019 Apr 10;20(7):1772. doi: 10.3390/ijms20071772.
• [10] Estrogen receptor activation contributes to RNF146 expression and neuroprotection in Parkinson's disease models.Oncotarget. 2017 Oct 11;8(63):106721-106739. doi: 10.18632/oncotarget.21828. eCollection 2017 Dec 5.
• [11] KIT Mutation and Loss of 14q May Be Sufficient for the Development of Clinically Symptomatic Very Low-Risk GIST.PLoS One. 2015 Jun 23;10(6):e0130149. doi: 10.1371/journal.pone.0130149. eCollection 2015.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] 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.
• [18] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [19] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [20] Benzo[a]pyrene increases the Nrf2 content by downregulating the Keap1 message. Toxicol Sci. 2010 Aug;116(2):549-61.
• [21] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.