Details of Drug Off-Target (DOT)

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

• DOT Name: Protein mago nashi homolog (MAGOH)
• Gene Name: MAGOH
• Related Disease:
  Esophageal cancer
  Advanced cancer
• UniProt ID: MGN_HUMAN
• PDB ID: 1P27; 2HYI; 2J0Q; 2J0S; 2XB2; 3EX7; 7A5P; 7W59; 7W5A; 7W5B; 7ZNJ; 8C6J
• Pfam ID: PF02792
• Sequence:
  MESDFYLRYYVGHKGKFGHEFLEFEFRPDGKLRYANNSNYKNDVMIRKEAYVHKSVMEEL
  KRIIDDSEITKEDDALWPPPDRVGRQELEIVIGDEHISFTTSKIGSLIDVNQSKDPEGLR
  VFYYLVQDLKCLVFSLIGLHFKIKPI
• Function: Required for pre-mRNA splicing as component of the spliceosome. Plays a redundant role with MAGOHB as core component of the exon junction complex (EJC) and in the nonsense-mediated decay (NMD) pathway. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). The MAGOH-RBM8A heterodimer inhibits the ATPase activity of EIF4A3, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The MAGOH-RBM8A heterodimer interacts with the EJC key regulator PYM1 leading to EJC disassembly in the cytoplasm and translation enhancement of EJC-bearing spliced mRNAs by recruiting them to the ribosomal 48S preinitiation complex. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  mR. surveillance pathway (hsa03015)
  Spliceosome (hsa03040)
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA 3'-end processing (R-HSA-72187)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal cancer	DISGB2VN	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Protein mago nashi homolog (MAGOH) affects the response to substance of Mitomycin.	[11]

7 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 Protein mago nashi homolog (MAGOH).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein mago nashi homolog (MAGOH).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein mago nashi homolog (MAGOH).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein mago nashi homolog (MAGOH).	[6]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Protein mago nashi homolog (MAGOH).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein mago nashi homolog (MAGOH).	[9]
PP-242	DM2348V	Investigative	PP-242 increases the expression of Protein mago nashi homolog (MAGOH).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein mago nashi homolog (MAGOH).	[8]

References

• [1] Physical and transcript map of the minimally deleted region III on 17p implicated in the early development of Barrett's oesophageal adenocarcinoma.Oncogene. 2003 Jun 26;22(26):4134-42. doi: 10.1038/sj.onc.1206466.
• [2] Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer.Nat Genet. 2018 Jul;50(7):937-943. doi: 10.1038/s41588-018-0155-3. Epub 2018 Jun 28.
• [3] 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.
• [4] 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.
• [5] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [6] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [7] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [8] 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.
• [9] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [10] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [11] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.