Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR6N7HU)

• DOT Name: E3 ubiquitin-protein ligase RNF113A (RNF113A)
• Synonyms: EC 2.3.2.27; Cwc24 homolog; RING finger protein 113A; Zinc finger protein 183
• Gene Name: RNF113A
• Related Disease:
  Advanced cancer
  Esophageal squamous cell carcinoma
  Neoplasm
  Trichothiodystrophy 5, nonphotosensitive
  Trichothiodystrophy
  Intellectual disability
• UniProt ID: R113A_HUMAN
• PDB ID: 5Z56; 5Z58; 6FF4; 6FF7; 7DVQ; 7QTT; 8CH6
• EC Number: 2.3.2.27
• Pfam ID: PF13920 ; PF00642
• Sequence:
  MAEQLSPGKAVDQVCTFLFKKPGRKGAAGRRKRPACDPEPGESGSSSDEGCTVVRPEKKR
  VTHNPMIQKTRDSGKQKAAYGDLSSEEEEENEPESLGVVYKSTRSAKPVGPEDMGATAVY
  ELDTEKERDAQAIFERSQKIQEELRGKEDDKIYRGINNYQKYMKPKDTSMGNASSGMVRK
  GPIRAPEHLRATVRWDYQPDICKDYKETGFCGFGDSCKFLHDRSDYKHGWQIERELDEGR
  YGVYEDENYEVGSDDEEIPFKCFICRQSFQNPVVTKCRHYFCESCALQHFRTTPRCYVCD
  QQTNGVFNPAKELIAKLEKHRATGEGGASDLPEDPDEDAIPIT
• Function: Required for pre-mRNA splicing as component of the spliceosome. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). E3 ubiquitin-protein ligase that catalyzes the transfer of ubiquitin onto target proteins. Catalyzes polyubiquitination of SNRNP200/BRR2 with non-canonical 'Lys-63'-linked polyubiquitin chains. Plays a role in DNA repair via its role in the synthesis of 'Lys-63'-linked polyubiquitin chains that recruit ALKBH3 and the ASCC complex to sites of DNA damage by alkylating agents. Ubiquitinates CXCR4, leading to its degradation, and thereby contributes to the termination of CXCR4 signaling.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Trichothiodystrophy 5, nonphotosensitive	DISC9HS8	Strong	X-linked	[2]
Trichothiodystrophy	DISOMQD2	Supportive	Autosomal recessive	[2]
Intellectual disability	DISMBNXP	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[8]

14 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 RNF113A (RNF113A).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[9]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[7]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[7]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[7]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[7]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase RNF113A (RNF113A).	[15]

References

• [1] RNF113A promotes the proliferation, migration and invasion, and is associated with a poor prognosis of esophageal squamous cell carcinoma.Int J Oncol. 2018 Mar;52(3):861-871. doi: 10.3892/ijo.2018.4253. Epub 2018 Jan 24.
• [2] A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A. J Med Genet. 2015 Apr;52(4):269-74. doi: 10.1136/jmedgenet-2014-102418. Epub 2015 Jan 22.
• [3] A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair.Nature. 2017 Nov 16;551(7680):389-393. doi: 10.1038/nature24484. Epub 2017 Nov 8.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [8] 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.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] 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.
• [13] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [14] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.