Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQY58LU)

• DOT Name: E3 ubiquitin-protein ligase RNF34 (RNF34)
• Synonyms: EC 2.3.2.27; Caspase regulator CARP1; Caspases-8 and -10-associated RING finger protein 1; CARP-1; FYVE-RING finger protein Momo; Human RING finger homologous to inhibitor of apoptosis protein; hRFI; RING finger protein 34; RING finger protein RIFF; RING-type E3 ubiquitin transferase RNF34
• Gene Name: RNF34
• UniProt ID: RNF34_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF21272 ; PF13920
• Sequence:
  MKAGATSMWASCCGLLNEVMGTGAVRGQQSAFAGATGPFRFTPNPEFSTYPPAATEGPNI
  VCKACGLSFSVFRKKHVCCDCKKDFCSVCSVLQENLRRCSTCHLLQETAFQRPQLMRLKV
  KDLRQYLILRNIPIDTCREKEDLVDLVLCHHGLGSEDDMDTSSLNSSRSQTSSFFTRSFF
  SNYTAPSATMSSFQGELMDGDQTSRSGVPAQVQSEITSANTEDDDDDDDEDDDDEEENAE
  DRNPGLSKERVRASLSDLSSLDDVEGMSVRQLKEILARNFVNYSGCCEKWELVEKVNRLY
  KENEENQKSYGERLQLQDEEDDSLCRICMDAVIDCVLLECGHMVTCTKCGKRMSECPICR
  QYVVRAVHVFKS
• Function: E3 ubiquitin-protein ligase that regulates several biological processes through the ubiquitin-mediated proteasomal degradation of various target proteins. Ubiquitinates the caspases CASP8 and CASP10, promoting their proteasomal degradation, to negatively regulate cell death downstream of death domain receptors in the extrinsic pathway of apoptosis. May mediate 'Lys-48'-linked polyubiquitination of RIPK1 and its subsequent proteasomal degradation thereby indirectly regulating the tumor necrosis factor-mediated signaling pathway (Ref.13). Negatively regulates p53/TP53 through its direct ubiquitination and targeting to proteasomal degradation. Indirectly, may also negatively regulate p53/TP53 through ubiquitination and degradation of SFN. Mediates PPARGC1A proteasomal degradation probably through ubiquitination thereby indirectly regulating the metabolism of brown fat cells. Possibly involved in innate immunity, through 'Lys-48'-linked polyubiquitination of NOD1 and its subsequent proteasomal degradation.
• Tissue Specificity: Ubiquitous. Detected in heart, brain, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, colon and leukocytes.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Regulation of TP53 Degradation (R-HSA-6804757)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	E3 ubiquitin-protein ligase RNF34 (RNF34) decreases the response to substance of Cisplatin.	[10]
Fluorouracil	DMUM7HZ	Approved	E3 ubiquitin-protein ligase RNF34 (RNF34) decreases the response to substance of Fluorouracil.	[10]
Irinotecan	DMP6SC2	Approved	E3 ubiquitin-protein ligase RNF34 (RNF34) decreases the response to substance of Irinotecan.	[10]

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 E3 ubiquitin-protein ligase RNF34 (RNF34).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase RNF34 (RNF34).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase RNF34 (RNF34).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of E3 ubiquitin-protein ligase RNF34 (RNF34).	[6]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of E3 ubiquitin-protein ligase RNF34 (RNF34).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of E3 ubiquitin-protein ligase RNF34 (RNF34).	[8]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of E3 ubiquitin-protein ligase RNF34 (RNF34).	[9]

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 RNF34 (RNF34).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of E3 ubiquitin-protein ligase RNF34 (RNF34).	[5]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 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.
• [5] 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.
• [6] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [7] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.
• [10] Exogenous expression of hRFI induces multidrug resistance through escape from apoptosis in colorectal cancer cells. Anticancer Res. 2005 Jul-Aug;25(4):2737-41.