Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCG27CT)

• DOT Name: E3 ubiquitin-protein ligase RNF144A (RNF144A)
• Synonyms: EC 2.3.2.31; RING finger protein 144A; UbcM4-interacting protein 4; Ubiquitin-conjugating enzyme 7-interacting protein 4
• Gene Name: RNF144A
• Related Disease:
  Breast neoplasm
  Neoplasm
  Advanced cancer
  Breast cancer
  Breast carcinoma
• UniProt ID: R144A_HUMAN
• PDB ID: 1WIM; 6L99
• EC Number: 2.3.2.31
• Pfam ID: PF01485
• Sequence:
  MTTTRYRPTWDLALDPLVSCKLCLGEYPVEQMTTIAQCQCIFCTLCLKQYVELLIKEGLE
  TAISCPDAACPKQGHLQENEIECMVAAEIMQRYKKLQFEREVLFDPCRTWCPASTCQAVC
  QLQDVGLQTPQPVQCKACRMEFCSTCKASWHPGQGCPETMPITFLPGETSAAFKMEEDDA
  PIKRCPKCKVYIERDEGCAQMMCKNCKHAFCWYCLESLDDDFLLIHYDKGPCRNKLGHSR
  ASVIWHRTQVVGIFAGFGLLLLVASPFLLLATPFVLCCKCKCSKGDDDPLPT
• Function: E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes UBE2L3 and UBE2L6 in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates the ubiquitination and degradation of the DNA damage kinase PRKDC during DNA damage. Positively regulates DNA virus or exogenous cytosolic DNA-triggered innate immune response by mediating STING1 ubiquitination and increasing its 'Lys-6'-linked ubiquitination and translocation from the endoplasmic reticulum to the Golgi leading to downstream signaling pathways. Plays a positive role in EGF-dependent cell proliferation by prolonging EGF/EGFR signaling during EGF stimulation through EGFR ubiquitination. Increases ERK activity independently of EGFR signaling by promoting polyubiquitination and subsequent degradation of VRK3 in the cytosol.
• Reactome Pathway: E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[1]
Breast cancer	DIS7DPX1	moderate	Biomarker	[1]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[9]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of E3 ubiquitin-protein ligase RNF144A (RNF144A).	[13]

References

• [1] RNF144A functions as a tumor suppressor in breast cancer through ubiquitin ligase activity-dependent regulation of stability and oncogenic functions of HSPA2.Cell Death Differ. 2020 Mar;27(3):1105-1118. doi: 10.1038/s41418-019-0400-z. Epub 2019 Aug 13.
• [2] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [6] Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults. Environ Health Perspect. 2019 May;127(5):57011. doi: 10.1289/EHP3849. Epub 2019 May 28.
• [7] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [11] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.