Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMDBLP4)

• DOT Name: RING-box protein 2 (RNF7)
• Synonyms: Rbx2; CKII beta-binding protein 1; CKBBP1; RING finger protein 7; Regulator of cullins 2; Sensitive to apoptosis gene protein
• Gene Name: RNF7
• UniProt ID: RBX2_HUMAN
• PDB ID: 2ECL; 7ONI
• Pfam ID: PF12678
• Sequence:
  MADVEDGEETCALASHSGSSGSKSGGDKMFSLKKWNAVAMWSWDVECDTCAICRVQVMDA
  CLRCQAENKQEDCVVVWGECNHSFHNCCMSLWVKQNNRCPLCQQDWVVQRIGK
• Function: Probable component of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins involved in cell cycle progression, signal transduction and transcription. CRLs complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins, ARIH1 mediating addition of the first ubiquitin on CRLs targets. Through the RING-type zinc finger, seems to recruit the E2 ubiquitination enzyme to the complex and brings it into close proximity to the substrate. Promotes the neddylation of CUL5 via its interaction with UBE2F. May play a role in protecting cells from apoptosis induced by redox agents.
• Tissue Specificity: Expressed in heart, liver, skeletal muscle and pancreas. At very low levels expressed in brain, placenta and lung.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  Inactivation of CSF3 (G-CSF) signaling (R-HSA-9705462)
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

7 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 RING-box protein 2 (RNF7).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of RING-box protein 2 (RNF7).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RING-box protein 2 (RNF7).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of RING-box protein 2 (RNF7).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of RING-box protein 2 (RNF7).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RING-box protein 2 (RNF7).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of RING-box protein 2 (RNF7).	[8]

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 RING-box protein 2 (RNF7).	[7]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Investigative	4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole decreases the phosphorylation of RING-box protein 2 (RNF7).	[9]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] 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.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [9] CK2 phosphorylation of SAG at Thr10 regulates SAG stability, but not its E3 ligase activity. Mol Cell Biochem. 2007 Jan;295(1-2):179-88. doi: 10.1007/s11010-006-9287-3. Epub 2006 Jul 28.