Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT67SRZ)

• DOT Name: Nucleolar protein 56 (NOP56)
• Synonyms: Nucleolar protein 5A
• Gene Name: NOP56
• Related Disease:
  Spinocerebellar ataxia type 36
  Burkitt lymphoma
  Cardiac arrest
  Cerebellar ataxia
  Cerebellar disorder
  Fragile X-associated tremor/ataxia syndrome
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Lung adenocarcinoma
  Motor neurone disease
  Neoplasm
  Sensorineural hearing loss disorder
  Amyotrophic lateral sclerosis
  Colorectal carcinoma
  Age-related macular degeneration
  Hereditary spastic paraplegia
• UniProt ID: NOP56_HUMAN
• PDB ID: 7MQ8; 7MQ9; 7MQA
• Pfam ID: PF01798 ; PF08156
• Sequence:
  MVLLHVLFEHAVGYALLALKEVEEISLLQPQVEESVLNLGKFHSIVRLVAFCPFASSQVA
  LENANAVSEGVVHEDLRLLLETHLPSKKKKVLLGVGDPKIGAAIQEELGYNCQTGGVIAE
  ILRGVRLHFHNLVKGLTDLSACKAQLGLGHSYSRAKVKFNVNRVDNMIIQSISLLDQLDK
  DINTFSMRVREWYGYHFPELVKIINDNATYCRLAQFIGNRRELNEDKLEKLEELTMDGAK
  AKAILDASRSSMGMDISAIDLINIESFSSRVVSLSEYRQSLHTYLRSKMSQVAPSLSALI
  GEAVGARLIAHAGSLTNLAKYPASTVQILGAEKALFRALKTRGNTPKYGLIFHSTFIGRA
  AAKNKGRISRYLANKCSIASRIDCFSEVPTSVFGEKLREQVEERLSFYETGEIPRKNLDV
  MKEAMVQAEEAAAEITRKLEKQEKKRLKKEKKRLAALALASSENSSSTPEECEEMSEKPK
  KKKKQKPQEVPQENGMEDPSISFSKPKKKKSFSKEELMSSDLEETAGSTSIPKRKKSTPK
  EETVNDPEEAGHRSGSKKKRKFSKEEPVSSGPEEAVGKSSSKKKKKFHKASQED
• Function: Involved in the early to middle stages of 60S ribosomal subunit biogenesis. Core component of box C/D small nucleolar ribonucleoprotein (snoRNP) particles. Required for the biogenesis of box C/D snoRNAs such U3, U8 and U14 snoRNAs. 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)
  Spinocerebellar ataxia (hsa05017)
• Reactome Pathway:
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spinocerebellar ataxia type 36	DISP7IPL	Definitive	Autosomal dominant	[1]
Burkitt lymphoma	DIS9D5XU	Strong	Biomarker	[2]
Cardiac arrest	DIS9DIA4	Strong	Biomarker	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[4]
Cerebellar disorder	DIS2O7WM	Strong	Biomarker	[3]
Fragile X-associated tremor/ataxia syndrome	DISKB25R	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[6]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[6]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[7]
Motor neurone disease	DISUHWUI	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[3]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Genetic Variation	[9]
Colorectal carcinoma	DIS5PYL0	Disputed	Biomarker	[10]
Age-related macular degeneration	DIS0XS2C	Limited	Posttranslational Modification	[11]
Hereditary spastic paraplegia	DISGZQV1	Limited	Genetic Variation	[9]

16 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 Nucleolar protein 56 (NOP56).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nucleolar protein 56 (NOP56).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nucleolar protein 56 (NOP56).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nucleolar protein 56 (NOP56).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nucleolar protein 56 (NOP56).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Nucleolar protein 56 (NOP56).	[17]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Nucleolar protein 56 (NOP56).	[18]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Nucleolar protein 56 (NOP56).	[19]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Nucleolar protein 56 (NOP56).	[17]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Nucleolar protein 56 (NOP56).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Nucleolar protein 56 (NOP56).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Nucleolar protein 56 (NOP56).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Nucleolar protein 56 (NOP56).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Nucleolar protein 56 (NOP56).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nucleolar protein 56 (NOP56).	[25]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Nucleolar protein 56 (NOP56).	[21]

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 Nucleolar protein 56 (NOP56).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nucleolar protein 56 (NOP56).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Nucleolar protein 56 (NOP56).	[24]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Nucleolar protein 56 (NOP56).	[26]

References

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• [2] Burkitt's lymphoma-associated c-Myc mutations converge on a dramatically altered target gene response and implicate Nol5a/Nop56 in oncogenesis.Oncogene. 2014 Jul 3;33(27):3519-27. doi: 10.1038/onc.2013.338. Epub 2013 Sep 9.
• [3] PET and MRI detection of early and progressive neurodegeneration in spinocerebellar ataxia type 36.Mov Disord. 2017 Feb;32(2):264-273. doi: 10.1002/mds.26854. Epub 2016 Nov 10.
• [4] Suppression of the yeast elongation factor Spt4 ortholog reduces expanded SCA36 GGCCUG repeat aggregation and cytotoxicity.Brain Res. 2019 May 15;1711:29-40. doi: 10.1016/j.brainres.2018.12.045. Epub 2019 Jan 2.
• [5] Frequency of SCA8, SCA10, SCA12, SCA36, FXTAS and C9orf72 repeat expansions in SCA patients negative for the most common SCA subtypes.BMC Neurol. 2018 Jan 9;18(1):3. doi: 10.1186/s12883-017-1009-9.
• [6] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [7] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [8] Assessment of swallowing in motor neuron disease and Asidan/SCA36 patients with new methods.J Neurol Sci. 2013 Jan 15;324(1-2):149-55. doi: 10.1016/j.jns.2012.10.025. Epub 2012 Nov 10.
• [9] Genetic and clinical analysis of spinocerebellar ataxia type 36 in Mainland China.Clin Genet. 2016 Aug;90(2):141-8. doi: 10.1111/cge.12706. Epub 2016 Jan 20.
• [10] A genomic strategy for the functional validation of colorectal cancer genes identifies potential therapeutic targets.Int J Cancer. 2011 Mar 1;128(5):1069-79. doi: 10.1002/ijc.25453.
• [11] Identification of aberrantly methylated differentially expressed genes in age-related macular degeneration.Medicine (Baltimore). 2019 Apr;98(14):e15083. doi: 10.1097/MD.0000000000015083.
• [12] 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.
• [13] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [14] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [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] 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.
• [18] 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.
• [19] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [20] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [21] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.