Details of Drug Off-Target (DOT)

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

• DOT Name: Ribosomal RNA-processing protein 8 (RRP8)
• Synonyms: EC 2.1.1.-; Cerebral protein 1; Nucleomethylin
• Gene Name: RRP8
• Related Disease:
  Breast neoplasm
  Cystic fibrosis
  HIV-associated dementia
  Metabolic disorder
• UniProt ID: RRP8_HUMAN
• PDB ID: 2ZFU
• EC Number: 2.1.1.-
• Pfam ID: PF05148
• Sequence:
  MFEEPEWAEAAPVAAGLGPVISRPPPAASSQNKGSKRRQLLATLRALEAASLSQHPPSLC
  ISDSEEEEEERKKKCPKKASFASASAEVGKKGKKKCQKQGPPCSDSEEEVERKKKCHKQA
  LVGSDSAEDEKRKRKCQKHAPINSAQHLDNVDQTGPKAWKGSTTNDPPKQSPGSTSPKPP
  HTLSRKQWRNRQKNKRRCKNKFQPPQVPDQAPAEAPTEKTEVSPVPRTDSHEARAGALRA
  RMAQRLDGARFRYLNEQLYSGPSSAAQRLFQEDPEAFLLYHRGFQSQVKKWPLQPVDRIA
  RDLRQRPASLVVADFGCGDCRLASSIRNPVHCFDLASLDPRVTVCDMAQVPLEDESVDVA
  VFCLSLMGTNIRDFLEEANRVLKPGGLLKVAEVSSRFEDVRTFLRAVTKLGFKIVSKDLT
  NSHFFLFDFQKTGPPLVGPKAQLSGLQLQPCLYKRR
• Function: Essential component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. In the complex, RRP8 binds to H3K9me2 and probably acts as a methyltransferase. Its substrates are however unknown.
• Reactome Pathway: SIRT1 negatively regulates rRNA expression (R-HSA-427359)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[2]
HIV-associated dementia	DIS8OCOC	Strong	Genetic Variation	[3]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[4]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Ribosomal RNA-processing protein 8 (RRP8).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ribosomal RNA-processing protein 8 (RRP8).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ribosomal RNA-processing protein 8 (RRP8).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Ribosomal RNA-processing protein 8 (RRP8).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ribosomal RNA-processing protein 8 (RRP8).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ribosomal RNA-processing protein 8 (RRP8).	[11]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Ribosomal RNA-processing protein 8 (RRP8).	[12]

2 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 decreases the phosphorylation of Ribosomal RNA-processing protein 8 (RRP8).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Ribosomal RNA-processing protein 8 (RRP8).	[9]

References

• [1] Nucleolar repression facilitates initiation and maintenance of senescence.Cell Cycle. 2015;14(22):3613-23. doi: 10.1080/15384101.2015.1100777.
• [2] Tatumella saanichensis sp. nov., isolated from a cystic fibrosis patient.Int J Syst Evol Microbiol. 2015 Jun;65(Pt 6):1959-1966. doi: 10.1099/ijs.0.000207. Epub 2015 Mar 25.
• [3] Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain.Ann Neurol. 1997 Nov;42(5):689-98. doi: 10.1002/ana.410420504.
• [4] A single N(1)-methyladenosine on the large ribosomal subunit rRNA impacts locally its structure and the translation of key metabolic enzymes.Sci Rep. 2018 Aug 9;8(1):11904. doi: 10.1038/s41598-018-30383-z.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] 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.
• [10] 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.
• [11] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [12] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.