Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase RNF4 (RNF4)
• Synonyms: EC 2.3.2.27; RING finger protein 4; Small nuclear ring finger protein; Protein SNURF
• Gene Name: RNF4
• Related Disease:
  Respiratory syncytial virus infection
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Fanconi anemia complementation group A
  Fanconi's anemia
  Male breast carcinoma
  Male infertility
  Partial androgen insensitivity syndrome
  Promyelocytic leukaemia
  Autosomal dominant cerebellar ataxia type II
  Huntington disease
  Neoplasm
• UniProt ID: RNF4_HUMAN
• PDB ID: 2EA6; 2XEU; 4PPE
• EC Number: 2.3.2.27
• Pfam ID: PF13639
• Sequence:
  MSTRKRRGGAINSRQAQKRTREATSTPEISLEAEPIELVETAGDEIVDLTCESLEPVVVD
  LTHNDSVVIVDERRRPRRNARRLPQDHADSCVVSSDDEELSRDRDVYVTTHTPRNARDEG
  ATGLRPSGTVSCPICMDGYSEIVQNGRLIVSTECGHVFCSQCLRDSLKNANTCPTCRKKI
  NHKRYHPIYI
• Function: E3 ubiquitin-protein ligase which binds polysumoylated chains covalently attached to proteins and mediates 'Lys-6'-, 'Lys-11'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination of those substrates and their subsequent targeting to the proteasome for degradation. Regulates the degradation of several proteins including PML and the transcriptional activator PEA3. Involved in chromosome alignment and spindle assembly, it regulates the kinetochore CENPH-CENPI-CENPK complex by targeting polysumoylated CENPI to proteasomal degradation. Regulates the cellular responses to hypoxia and heat shock through degradation of respectively EPAS1 and PARP1. Alternatively, it may also bind DNA/nucleosomes and have a more direct role in the regulation of transcription for instance enhancing basal transcription and steroid receptor-mediated transcriptional activation. Catalyzes ubiquitination of sumoylated PARP1 in response to PARP1 trapping to chromatin, leading to PARP1 removal from chromatin by VCP/p97.
• Tissue Specificity: Widely expressed at low levels in many tissues; highly expressed in testis.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Processing of DNA double-strand break ends (R-HSA-5693607)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Respiratory syncytial virus infection	DIS7FWHY	Definitive	Altered Expression	[1]
Colon cancer	DISVC52G	Strong	Genetic Variation	[2]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[2]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[2]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[3]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[3]
Male breast carcinoma	DISUNQ2Q	Strong	Biomarker	[4]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[5]
Partial androgen insensitivity syndrome	DISQ1113	Strong	Genetic Variation	[4]
Promyelocytic leukaemia	DISYGG13	moderate	Biomarker	[6]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Limited	Biomarker	[7]
Huntington disease	DISQPLA4	Limited	Altered Expression	[8]
Neoplasm	DISZKGEW	Limited	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase RNF4 (RNF4).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase RNF4 (RNF4).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF4 (RNF4).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of E3 ubiquitin-protein ligase RNF4 (RNF4).	[14]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of E3 ubiquitin-protein ligase RNF4 (RNF4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase RNF4 (RNF4).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E3 ubiquitin-protein ligase RNF4 (RNF4).	[19]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the expression of E3 ubiquitin-protein ligase RNF4 (RNF4).	[13]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the localization of E3 ubiquitin-protein ligase RNF4 (RNF4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase RNF4 (RNF4).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of E3 ubiquitin-protein ligase RNF4 (RNF4).	[17]

References

• [1] Respiratory syncytial virus induces NRF2 degradation through a promyelocytic leukemia protein - ring finger protein 4 dependent pathway.Free Radic Biol Med. 2017 Dec;113:494-504. doi: 10.1016/j.freeradbiomed.2017.10.380. Epub 2017 Oct 28.
• [2] Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas.Oncotarget. 2017 Oct 9;8(58):98623-98634. doi: 10.18632/oncotarget.21697. eCollection 2017 Nov 17.
• [3] RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway.J Clin Invest. 2015 Apr;125(4):1523-32. doi: 10.1172/JCI79325. Epub 2015 Mar 9.
• [4] Coregulator small nuclear RING finger protein (SNURF) enhances Sp1- and steroid receptor-mediated transcription by different mechanisms.J Biol Chem. 2000 Jan 7;275(1):571-9. doi: 10.1074/jbc.275.1.571.
• [5] A Neofunctionalized X-Linked Ampliconic Gene Family Is Essential for Male Fertility and Equal Sex Ratio in Mice.Curr Biol. 2019 Nov 4;29(21):3699-3706.e5. doi: 10.1016/j.cub.2019.08.057. Epub 2019 Oct 17.
• [6] Arkadia (RING Finger Protein 111) Mediates Sumoylation-Dependent Stabilization of Nrf2 Through K48-Linked Ubiquitination.Cell Physiol Biochem. 2018;46(1):418-430. doi: 10.1159/000488475. Epub 2018 Mar 23.
• [7] SUMOylation by SUMO2 is implicated in the degradation of misfolded ataxin-7 via RNF4 in SCA7 models.Dis Model Mech. 2019 Jan 11;12(1):dmm036145. doi: 10.1242/dmm.036145.
• [8] SUMO-Targeted Ubiquitin Ligases (STUbLs) Reduce the Toxicity and Abnormal Transcriptional Activity Associated With a Mutant, Aggregation-Prone Fragment of Huntingtin.Front Genet. 2018 Sep 18;9:379. doi: 10.3389/fgene.2018.00379. eCollection 2018.
• [9] An integrated approach of immunogenomics and bioinformatics to identify new Tumor Associated Antigens (TAA) for mammary cancer immunological prevention.BMC Bioinformatics. 2005 Dec 1;6 Suppl 4(Suppl 4):S7. doi: 10.1186/1471-2105-6-S4-S7.
• [10] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] 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.
• [13] Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies. Mol Biol Cell. 2010 Dec;21(23):4227-39. doi: 10.1091/mbc.E10-05-0449. Epub 2010 Oct 13.
• [14] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [15] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [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] 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.
• [18] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [19] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.