Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT97EAV4)

• DOT Name: U3 small nucleolar RNA-interacting protein 2 (RRP9)
• Synonyms: RRP9 homolog; U3 small nucleolar ribonucleoprotein-associated 55 kDa protein; U3 snoRNP-associated 55 kDa protein; U3-55K
• Gene Name: RRP9
• Related Disease:
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
• UniProt ID: U3IP2_HUMAN
• PDB ID: 4J0W; 4JXM; 7MQ8; 7MQ9; 7MQA
• Pfam ID: PF00400
• Sequence:
  MSATAAARKRGKPASGAGAGAGAGKRRRKADSAGDRGKSKGGGKMNEEISSDSESESLAP
  RKPEEEEEEELEETAQEKKLRLAKLYLEQLRQQEEEKAEARAFEEDQVAGRLKEDVLEQR
  GRLQKLVAKEIQAPASADIRVLRGHQLSITCLVVTPDDSAIFSAAKDCSIIKWSVESGRK
  LHVIPRAKKGAEGKPPGHSSHVLCMAISSDGKYLASGDRSKLILIWEAQSCQHLYTFTGH
  RDAVSGLAFRRGTHQLYSTSHDRSVKVWNVAENSYVETLFGHQDAVAALDALSRECCVTA
  GGRDGTVRVWKIPEESQLVFYGHQGSIDCIHLINEEHMVSGADDGSVALWGLSKKRPLAL
  QREAHGLRGEPGLEQPFWISSVAALLNTDLVATGSHSSCVRLWQCGEGFRQLDLLCDIPL
  VGFINSLKFSSSGDFLVAGVGQEHRLGRWWRIKEARNSVCIIPLRRVPVPPAAGS
• Function: Component of a nucleolar small nuclear ribonucleoprotein particle (snoRNP) thought to participate in the processing and modification of pre-ribosomal RNA (pre-rRNA). 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.
• 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Strong	Biomarker	[1]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[1]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[1]

12 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 U3 small nucleolar RNA-interacting protein 2 (RRP9).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[8]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[13]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of U3 small nucleolar RNA-interacting protein 2 (RRP9).	[14]

References

• [1] 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.
• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [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] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [9] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [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] 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.