Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFDX7HY)

• DOT Name: Ribosomal RNA small subunit methyltransferase NEP1 (EMG1)
• Synonyms: EC 2.1.1.-; 18S rRNA (pseudouridine(1248)-N1)-methyltransferase; 18S rRNA Psi1248 methyltransferase; Nucleolar protein EMG1 homolog; Protein C2f; Ribosome biogenesis protein NEP1
• Gene Name: EMG1
• Related Disease:
  Childhood kidney Wilms tumor
  Neural tube defect
  Wilms tumor
  Bowen-Conradi syndrome
  Ewing sarcoma
  Hereditary North American Indian childhood cirrhosis
  HIV infectious disease
  Scleroderma
  Systemic sclerosis
  Clear cell adenocarcinoma
  Neoplasm
  Stroke
• UniProt ID: NEP1_HUMAN
• PDB ID: 5FAI; 7MQ8; 7MQ9; 7MQA
• EC Number: 2.1.1.-
• Pfam ID: PF03587
• Sequence:
  MAAPSDGFKPRERSGGEQAQDWDALPPKRPRLGAGNKIGGRRLIVVLEGASLETVKVGKT
  YELLNCDKHKSILLKNGRDPGEARPDITHQSLLMLMDSPLNRAGLLQVYIHTQKNVLIEV
  NPQTRIPRTFDRFCGLMVQLLHKLSVRAADGPQKLLKVIKNPVSDHFPVGCMKVGTSFSI
  PVVSDVRELVPSSDPIVFVVGAFAHGKVSVEYTEKMVSISNYPLSAALTCAKLTTAFEEV
  WGVI
• Function: S-adenosyl-L-methionine-dependent pseudouridine N(1)-methyltransferase that methylates pseudouridine at position 1248 (Psi1248) in 18S rRNA. Involved the biosynthesis of the hypermodified N1-methyl-N3-(3-amino-3-carboxypropyl) pseudouridine (m1acp3-Psi) conserved in eukaryotic 18S rRNA. Is not able to methylate uridine at this position. Has also an essential role in 40S ribosomal subunit biogenesis independent on its methyltransferase activity, facilitating the incorporation of ribosomal protein S19 during the formation of pre-ribosomes. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)
• Reactome Pathway:
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Childhood kidney Wilms tumor	DIS0NMK3	Definitive	Biomarker	[1]
Neural tube defect	DIS5J95E	Definitive	Genetic Variation	[2]
Wilms tumor	DISB6T16	Definitive	Biomarker	[1]
Bowen-Conradi syndrome	DIS2MEY5	Strong	Autosomal recessive	[3]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[4]
Hereditary North American Indian childhood cirrhosis	DISBJ6T5	Strong	Biomarker	[5]
HIV infectious disease	DISO97HC	Strong	Biomarker	[6]
Scleroderma	DISVQ342	Strong	Biomarker	[5]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[5]
Clear cell adenocarcinoma	DISYUGHZ	Limited	Biomarker	[7]
Neoplasm	DISZKGEW	Limited	Biomarker	[8]
Stroke	DISX6UHX	Limited	Biomarker	[9]

14 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 Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ribosomal RNA small subunit methyltransferase NEP1 (EMG1).	[22]

References

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• [2] Growth arrest in the ribosomopathy, Bowen-Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression.Biochim Biophys Acta. 2015 May;1852(5):1029-37. doi: 10.1016/j.bbadis.2015.02.007. Epub 2015 Feb 20.
• [3] Effects of the Bowen-Conradi syndrome mutation in EMG1 on its nuclear import, stability and nucleolar recruitment. Hum Mol Genet. 2016 Dec 15;25(24):5353-5364. doi: 10.1093/hmg/ddw351.
• [4] Retracted: Long Noncoding RNA SOX2OT Accelerates the Carcinogenesis of Wilms' Tumor Through ceRNA Through miR-363/FOXP4 Axis.DNA Cell Biol. 2018 Nov 27. doi: 10.1089/dna.2018.4420. Online ahead of print.
• [5] Human diseases of the SSU processome.Biochim Biophys Acta. 2014 Jun;1842(6):758-64. doi: 10.1016/j.bbadis.2013.11.004. Epub 2013 Nov 12.
• [6] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [7] Correlation between pre-operative and final histological diagnosis on endometrial cancer.Int J Gynecol Cancer. 2019 Jun;29(5):886-889. doi: 10.1136/ijgc-2018-000041. Epub 2019 Jan 4.
• [8] Molecular Mechanism of the Cell Death Induced by the Histone Deacetylase Pan Inhibitor LBH589 (Panobinostat) in Wilms Tumor Cells.PLoS One. 2015 Jul 15;10(7):e0126566. doi: 10.1371/journal.pone.0126566. eCollection 2015.
• [9] Constraint-induced movement therapy enhances angiogenesis and neurogenesis after cerebral ischemia/reperfusion.Neural Regen Res. 2019 Oct;14(10):1743-1754. doi: 10.4103/1673-5374.257528.
• [10] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [15] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [16] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] 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.
• [23] 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.