Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR1XEZ3)

• DOT Name: E3 ubiquitin-protein ligase RNF216 (RNF216)
• Synonyms: EC 2.3.2.27; RING finger protein 216; RING-type E3 ubiquitin transferase RNF216; Triad domain-containing protein 3; Ubiquitin-conjugating enzyme 7-interacting protein 1; Zinc finger protein inhibiting NF-kappa-B
• Gene Name: RNF216
• Related Disease:
  Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
  Bruton-type agammaglobulinemia
  Cerebellar ataxia
  Cerebellar ataxia-hypogonadism syndrome
  Choreatic disease
  Colorectal carcinoma
  Hypogonadotropic hypogonadism
  Klinefelter syndrome
  Male infertility
  McCune-Albright syndrome
  Movement disorder
  Neoplasm
  Obesity
• UniProt ID: RN216_HUMAN
• PDB ID: 7M4M; 7M4N; 7M4O; 8EB0
• EC Number: 2.3.2.27
• Sequence:
  MEEGNNNEEVIHLNNFHCHRGQEWINLRDGPITISDSSDEERIPMLVTPAPQQHEEEDLD
  DDVILTEDDSEDDYGEFLDLGPPGISEFTKPSGQTEREPKPGPSHNQAANDIVNPRSEQK
  VIILEEGSLLYTESDPLETQNQSSEDSETELLSNLGESAALADDQAIEEDCWLDHPYFQS
  LNQQPREITNQVVPQERQPEAELGRLLFQHEFPGPAFPRPEPQQGGISGPSSPQPAHPLG
  EFEDQQLASDDEEPGPAFPMQESQEPNLENIWGQEAAEVDQELVELLVKETEARFPDVAN
  GFIEEIIHFKNYYDLNVLCNFLLENPDYPKREDRIIINPSSSLLASQDETKLPKIDFFDY
  SKLTPLDQRCFIQAADLLMADFKVLSSQDIKWALHELKGHYAITRKALSDAIKKWQELSP
  ETSGKRKKRKQMNQYSYIDFKFEQGDIKIEKRMFFLENKRRHCRSYDRRALLPAVQQEQE
  FYEQKIKEMAEHEDFLLALQMNEEQYQKDGQLIECRCCYGEFPFEELTQCADAHLFCKEC
  LIRYAQEAVFGSGKLELSCMEGSCTCSFPTSELEKVLPQTILYKYYERKAEEEVAAAYAD
  ELVRCPSCSFPALLDSDVKRFSCPNPHCRKETCRKCQGLWKEHNGLTCEELAEKDDIKYR
  TSIEEKMTAARIRKCHKCGTGLIKSEGCNRMSCRCGAQMCYLCRVSINGYDHFCQHPRSP
  GAPCQECSRCSLWTDPTEDDEKLIEEIQKEAEEEQKRKNGENTFKRIGPPLEKPVEKVQR
  VEALPRPVPQNLPQPQMPPYAFAHPPFPLPPVRPVFNNFPLNMGPIPAPYVPPLPNVRVN
  YDFGPIHMPLEHNLPMHFGPQPRHRF
• Function: [Isoform 1]: E3 ubiquitin ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their ubiquitination. Plays a role in the regulation of antiviral responses by promoting the degradation of TRAF3, TLR4 and TLR9. In turn, down-regulates NF-kappa-B and IRF3 activation as well as beta interferon production. Participates also in the regulation of autophagy by ubiquitinating BECN1 leading to its degradation and autophagy inhibition. Plays a role in ARC-dependent synaptic plasticity by mediating ARC ubiquitination resulting in its rapid proteasomal degradation. Plays aso an essential role in spermatogenesis and male fertility. Mechanistically, regulates meiosis by promoting the degradation of PRKACB through the ubiquitin-mediated lysosome pathway. Modulates the gonadotropin-releasing hormone signal pathway by affecting the stability of STAU2 that is required for the microtubule-dependent transport of neuronal RNA from the cell body to the dendrite; [Isoform 3]: Inhibits TNF and IL-1 mediated activation of NF-kappa-B. Promotes TNF and RIP mediated apoptosis.
• Tissue Specificity: Ubiquitous, with the highest levels of expression in testis and peripheral blood leukocytes.
• Reactome Pathway: Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome	DISM7VEP	Definitive	Genetic Variation	[1]
Bruton-type agammaglobulinemia	DISQ5ZYP	Strong	Altered Expression	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[3]
Cerebellar ataxia-hypogonadism syndrome	DISUEBFP	Strong	Autosomal recessive	[4]
Choreatic disease	DISH8K3M	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Hypogonadotropic hypogonadism	DIS8JSKR	Strong	Biomarker	[6]
Klinefelter syndrome	DISOUI7W	Strong	Biomarker	[6]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[7]
McCune-Albright syndrome	DISCO2QT	Strong	Genetic Variation	[8]
Movement disorder	DISOJJ2D	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Obesity	DIS47Y1K	Strong	Altered Expression	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF216 (RNF216).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase RNF216 (RNF216).	[13]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of E3 ubiquitin-protein ligase RNF216 (RNF216).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase RNF216 (RNF216).	[17]

3 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 RNF216 (RNF216).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase RNF216 (RNF216).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase RNF216 (RNF216).	[16]

References

• [1] Mutations in RNF216 do not cause 4H syndrome.Parkinsonism Relat Disord. 2015 Nov;21(11):1387-8. doi: 10.1016/j.parkreldis.2015.09.014. Epub 2015 Sep 4.
• [2] Disturbed Transcription of TLRs' Negative Regulators and Cytokines Secretion among TLR4- and 9-Activated PBMCs of Agammaglobulinemic Patients.Immunol Invest. 2019 Nov;48(8):860-874. doi: 10.1080/08820139.2019.1604742. Epub 2019 Jun 11.
• [3] RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder.Neurology. 2015 Apr 28;84(17):1760-6. doi: 10.1212/WNL.0000000000001521. Epub 2015 Apr 3.
• [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] RNF216 contributes to proliferation and migration of colorectal cancer via suppressing BECN1-dependent autophagy.Oncotarget. 2016 Aug 9;7(32):51174-51183. doi: 10.18632/oncotarget.9433.
• [6] RNF216 Regulates the Migration of Immortalized GnRH Neurons by Suppressing Beclin1-Mediated Autophagy.Front Endocrinol (Lausanne). 2019 Jan 24;10:12. doi: 10.3389/fendo.2019.00012. eCollection 2019.
• [7] RNF216 is essential for spermatogenesis and male fertility?"Melnick AF. Liu J
• [8] Genetic and molecular aspects of McCune-Albright syndrome.Pediatr Endocrinol Rev. 2007 Aug;4 Suppl 4:380-5.
• [9] TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation.Aging Cell. 2017 Apr;16(2):281-292. doi: 10.1111/acel.12551. Epub 2016 Dec 20.
• [10] Expression of two inflammation-related genes (RIPK3 and RNF216) in mononuclear cells is associated with weight-loss regain in obese subjects.J Nutrigenet Nutrigenomics. 2009;2(2):78-84. doi: 10.1159/000210452. Epub 2009 Apr 2.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [15] 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.
• [16] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [17] 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.