Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT54V3QN)

• DOT Name: Probable 28S rRNA (NOP2)
• Synonyms: cytosine(4447)-C(5))-methyltransferase (EC 2.1.1.-; Nucleolar protein 1; Nucleolar protein 2 homolog; Proliferating-cell nucleolar antigen p120; Proliferation-associated nucleolar protein p120
• Gene Name: NOP2
• UniProt ID: NOP2_HUMAN
• PDB ID: 8FKT; 8FKU; 8FKV; 8FKW; 8FKX; 8FKY
• EC Number: 2.1.1.-
• Pfam ID: PF01189 ; PF17125 ; PF08062
• Sequence:
  MGRKLDPTKEKRGPGRKARKQKGAETELVRFLPAVSDENSKRLSSRARKRAAKRRLGSVE
  APKTNKSPEAKPLPGKLPKGISAGAVQTAGKKGPQSLFNAPRGKKRPAPGSDEEEEEEDS
  EEDGMVNHGDLWGSEDDADTVDDYGADSNSEDEEEGEALLPIERAARKQKAREAAAGIQW
  SEEETEDEEEEKEVTPESGPPKVEEADGGLQINVDEEPFVLPPAGEMEQDAQAPDLQRVH
  KRIQDIVGILRDFGAQREEGRSRSEYLNRLKKDLAIYYSYGDFLLGKLMDLFPLSELVEF
  LEANEVPRPVTLRTNTLKTRRRDLAQALINRGVNLDPLGKWSKTGLVVYDSSVPIGATPE
  YLAGHYMLQGASSMLPVMALAPQEHERILDMCCAPGGKTSYMAQLMKNTGVILANDANAE
  RLKSVVGNLHRLGVTNTIISHYDGRQFPKVVGGFDRVLLDAPCSGTGVISKDPAVKTNKD
  EKDILRCAHLQKELLLSAIDSVNATSKTGGYLVYCTCSITVEENEWVVDYALKKRNVRLV
  PTGLDFGQEGFTRFRERRFHPSLRSTRRFYPHTHNMDGFFIAKFKKFSNSIPQSQTGNSE
  TATPTNVDLPQVIPKSENSSQPAKKAKGAAKTKQQLQKQQHPKKASFQKLNGISKGADSE
  LSTVPSVTKTQASSSFQDSSQPAGKAEGIREPKVTGKLKQRSPKLQSSKKVAFLRQNAPP
  KGTDTQTPAVLSPSKTQATLKPKDHHQPLGRAKGVEKQQLPEQPFEKAAFQKQNDTPKGP
  QPPTVSPIRSSRPPPAKRKKSQSRGNSQLLLS
• Function: Involved in ribosomal large subunit assembly. S-adenosyl-L-methionine-dependent methyltransferase that specifically methylates the C(5) position of cytosine 4447 in 28S rRNA (Probable). May play a role in the regulation of the cell cycle and the increased nucleolar activity that is associated with the cell proliferation (Probable).
• Reactome Pathway:
  TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation (R-HSA-8869496)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)

Molecular Interaction Atlas (MIA) of This DOT

11 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 Probable 28S rRNA (NOP2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Probable 28S rRNA (NOP2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Probable 28S rRNA (NOP2).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Probable 28S rRNA (NOP2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Probable 28S rRNA (NOP2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable 28S rRNA (NOP2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Probable 28S rRNA (NOP2).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Probable 28S rRNA (NOP2).	[8]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Probable 28S rRNA (NOP2).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Probable 28S rRNA (NOP2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Probable 28S rRNA (NOP2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Probable 28S rRNA (NOP2).	[9]

4 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 decreases the sumoylation of Probable 28S rRNA (NOP2).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Probable 28S rRNA (NOP2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Probable 28S rRNA (NOP2).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Probable 28S rRNA (NOP2).	[13]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [10] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.