Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBN7RS8)

• DOT Name: 28S rRNA (NSUN5)
• Synonyms: cytosine-C(5))-methyltransferase (EC 2.1.1.-; NOL1-related protein; NOL1R; NOL1/NOP2/Sun domain family member 5; Williams-Beuren syndrome chromosomal region 20A protein
• Gene Name: NSUN5
• Related Disease:
  Adult glioblastoma
  Colon cancer
  Colon carcinoma
  Glioblastoma multiforme
  Acute leukaemia
  Adenocarcinoma
  Arteriosclerosis
  Atherosclerosis
  Capillary malformation-arteriovenous malformation syndrome
  Cognitive impairment
  Ductal carcinoma
  Glioma
  Invasive ductal breast carcinoma
  Lung cancer
  Lung carcinoma
  Mucinous adenocarcinoma
  Neoplasm
  Oral cancer
  Oral cavity carcinoma
  Pancreatic cancer
  Prostate disease
  Squamous cell carcinoma
  Stroke
  Advanced cancer
• UniProt ID: NSUN5_HUMAN
• PDB ID: 2B9E
• EC Number: 2.1.1.-
• Pfam ID: PF01189 ; PF21148 ; PF21153
• Sequence:
  MGLYAAAAGVLAGVESRQGSIKGLVYSSNFQNVKQLYALVCETQRYSAVLDAVIASAGLL
  RAEKKLRPHLAKVLVYELLLGKGFRGGGGRWKALLGRHQARLKAELARLKVHRGVSRNED
  LLEVGSRPGPASQLPRFVRVNTLKTCSDDVVDYFKRQGFSYQGRASSLDDLRALKGKHFL
  LDPLMPELLVFPAQTDLHEHPLYRAGHLILQDRASCLPAMLLDPPPGSHVIDACAAPGNK
  TSHLAALLKNQGKIFAFDLDAKRLASMATLLARAGVSCCELAEEDFLAVSPSDPRYHEVH
  YILLDPSCSGSGMPSRQLEEPGAGTPSPVRLHALAGFQQRALCHALTFPSLQRLVYSTCS
  LCQEENEDVVRDALQQNPGAFRLAPALPAWPHRGLSTFPGAEHCLRASPETTLSSGFFVA
  VIERVEVPR
• Function: S-adenosyl-L-methionine-dependent methyltransferase that specifically methylates the C(5) position of cytosine 3782 (m5C3782) in 28S rRNA. m5C3782 promotes protein translation without affecting ribosome biogenesis and fidelity. Required for corpus callosum and cerebral cortex development.
• Tissue Specificity: Ubiquitous . Detected in placenta, heart and skeletal muscle .

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Colon cancer	DISVC52G	Definitive	Altered Expression	[2]
Colon carcinoma	DISJYKUO	Definitive	Altered Expression	[2]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Acute leukaemia	DISDQFDI	Strong	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Capillary malformation-arteriovenous malformation syndrome	DISMN03Q	Strong	Genetic Variation	[6]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[7]
Ductal carcinoma	DIS15EA5	Strong	Biomarker	[8]
Glioma	DIS5RPEH	Strong	Posttranslational Modification	[9]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[10]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Mucinous adenocarcinoma	DISKNFE8	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Oral cancer	DISLD42D	Strong	Biomarker	[13]
Oral cavity carcinoma	DISZXMVL	Strong	Biomarker	[13]
Pancreatic cancer	DISJC981	Strong	Biomarker	[14]
Prostate disease	DISFVG19	Strong	Altered Expression	[15]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[4]
Stroke	DISX6UHX	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[2]

7 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 28S rRNA (NSUN5).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 28S rRNA (NSUN5).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 28S rRNA (NSUN5).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 28S rRNA (NSUN5).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 28S rRNA (NSUN5).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 28S rRNA (NSUN5).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of 28S rRNA (NSUN5).	[22]

2 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 increases the methylation of 28S rRNA (NSUN5).	[23]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of 28S rRNA (NSUN5).	[24]

References

• [1] Interleukin-8 Secreted by Glioblastoma Cells Induces Microvascular Hyperpermeability Through NO Signaling Involving S-Nitrosylation of VE-Cadherin and p120 in Endothelial Cells.Front Physiol. 2019 Aug 8;10:988. doi: 10.3389/fphys.2019.00988. eCollection 2019.
• [2] miR-223 promotes colon cancer by directly targeting p120 catenin.Oncotarget. 2017 Jul 25;8(38):63764-63779. doi: 10.18632/oncotarget.19541. eCollection 2017 Sep 8.
• [3] E2A-ZNF384 and NOL1-E2A fusion created by a cryptic t(12;19)(p13.3; p13.3) in acute leukemia.Leukemia. 2008 Apr;22(4):723-9. doi: 10.1038/sj.leu.2405084. Epub 2008 Jan 10.
• [4] Expression of nucleolar protein p120 in human lung cancer: difference in histological types as a marker for proliferation.Clin Cancer Res. 1997 Oct;3(10):1873-7.
• [5] p120 inhibits LPS/TNF-induced endothelial Ang2 synthesis and release in an NF-B independent fashion.Cytokine. 2019 Nov;123:154786. doi: 10.1016/j.cyto.2019.154786. Epub 2019 Jul 26.
• [6] RASA1 regulates the function of lymphatic vessel valves in mice.J Clin Invest. 2017 Jun 30;127(7):2569-2585. doi: 10.1172/JCI89607. Epub 2017 May 22.
• [7] Cognitive deficits in mice lacking Nsun5, a cytosine-5 RNA methyltransferase, with impairment of oligodendrocyte precursor cells.Glia. 2019 Apr;67(4):688-702. doi: 10.1002/glia.23565. Epub 2018 Nov 28.
• [8] Further evidence that E-cadherin is not a tumour suppressor gene in invasive ductal carcinoma of the breast: an immunohistochemical study.Histopathology. 2013 Apr;62(5):695-701. doi: 10.1111/his.12066. Epub 2013 Jan 24.
• [9] Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program.Acta Neuropathol. 2019 Dec;138(6):1053-1074. doi: 10.1007/s00401-019-02062-4. Epub 2019 Aug 19.
• [10] Correlation between E-cadherin and p120 expression in invasive ductal breast cancer with a lobular component and MRI findings.Virchows Arch. 2017 Dec;471(6):707-712. doi: 10.1007/s00428-017-2203-2. Epub 2017 Aug 4.
• [11] Invasive lobular carcinoma with extracellular mucin production and HER-2 overexpression: a case report and further case studies.Diagn Pathol. 2010 Jun 15;5:36. doi: 10.1186/1746-1596-5-36.
• [12] p120-catenin in cancer - mechanisms, models and opportunities for intervention.J Cell Sci. 2013 Aug 15;126(Pt 16):3515-25. doi: 10.1242/jcs.134411.
• [13] Nucleolar protein p120 expression in oral carcinoma.Anticancer Res. 1999 Mar-Apr;19(2B):1423-6.
• [14] Up-regulation, nuclear import, and tumor growth stimulation of the adhesion protein p120 in pancreatic cancer.Gastroenterology. 2003 Apr;124(4):949-60. doi: 10.1053/gast.2003.50142.
• [15] A novel splice variant of the nuclear coactivator p120 functions strongly for androgen receptor: characteristic expression in prostate disease.Endocr J. 2008 Aug;55(4):657-65. doi: 10.1507/endocrj.k07e-133. Epub 2008 Jun 18.
• [16] 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.
• [17] 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.
• [18] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [19] 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.
• [20] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.