Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0K3TMH)

• DOT Name: Small ribosomal subunit protein uS3 (RPS3)
• Synonyms: 40S ribosomal protein S3; EC 4.2.99.18
• Gene Name: RPS3
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Melanoma
  Neoplasm
  Non-small-cell lung cancer
  Bone osteosarcoma
  Chronic obstructive pulmonary disease
  Osteosarcoma
  Werner syndrome
  Advanced cancer
  Asthma
  Osteoarthritis
• UniProt ID: RS3_HUMAN
• PDB ID: 1WH9 ; 4UG0 ; 4V6X ; 5A2Q ; 5AJ0 ; 5FLX ; 5LKS ; 5OA3 ; 5T2C ; 5VYC ; 6FEC ; 6G51 ; 6G53 ; 6G5H ; 6G5I ; 6IP5 ; 6IP6 ; 6IP8 ; 6OLE ; 6OLF ; 6OLG ; 6OLI ; 6OLZ ; 6OM0 ; 6OM7 ; 6QZP ; 6XA1 ; 6Y0G ; 6Y2L ; 6Y57 ; 6YBS ; 6Z6L ; 6Z6M ; 6Z6N ; 6ZLW ; 6ZM7 ; 6ZME ; 6ZMI ; 6ZMO ; 6ZMT ; 6ZMW ; 6ZN5 ; 6ZOJ ; 6ZOL ; 6ZON ; 6ZP4 ; 6ZUO ; 6ZV6 ; 6ZVH ; 6ZVJ ; 6ZXD ; 6ZXE ; 6ZXF ; 6ZXG ; 6ZXH ; 7A09 ; 7K5I ; 7QP6 ; 7QP7 ; 7QVP ; 7R4X ; 7TQL ; 7XNX ; 7XNY ; 8G5Y ; 8G5Z ; 8G60 ; 8G61 ; 8G6J ; 8GLP ; 8JDJ ; 8JDK ; 8JDL ; 8JDM ; 8PPK ; 8PPL ; 8T4S
• EC Number: 4.2.99.18
• Pfam ID: PF07650 ; PF00189
• Sequence:
  MAVQISKKRKFVADGIFKAELNEFLTRELAEDGYSGVEVRVTPTRTEIIILATRTQNVLG
  EKGRRIRELTAVVQKRFGFPEGSVELYAEKVATRGLCAIAQAESLRYKLLGGLAVRRACY
  GVLRFIMESGAKGCEVVVSGKLRGQRAKSMKFVDGLMIHSGDPVNYYVDTAVRHVLLRQG
  VLGIKVKIMLPWDPTGKIGPKKPLPDHVSIVEPKDEILPTTPISEQKGGKPEPPAMPQPV
  PTA
• Function: Component of the small ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. Has endonuclease activity and plays a role in repair of damaged DNA. Cleaves phosphodiester bonds of DNAs containing altered bases with broad specificity and cleaves supercoiled DNA more efficiently than relaxed DNA. Displays high binding affinity for 7,8-dihydro-8-oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species (ROS). Has also been shown to bind with similar affinity to intact and damaged DNA. Stimulates the N-glycosylase activity of the base excision protein OGG1. Enhances the uracil excision activity of UNG1. Also stimulates the cleavage of the phosphodiester backbone by APEX1. When located in the mitochondrion, reduces cellular ROS levels and mitochondrial DNA damage. Has also been shown to negatively regulate DNA repair in cells exposed to hydrogen peroxide. Plays a role in regulating transcription as part of the NF-kappa-B p65-p50 complex where it binds to the RELA/p65 subunit, enhances binding of the complex to DNA and promotes transcription of target genes. Represses its own translation by binding to its cognate mRNA. Binds to and protects TP53/p53 from MDM2-mediated ubiquitination. Involved in spindle formation and chromosome movement during mitosis by regulating microtubule polymerization. Involved in induction of apoptosis through its role in activation of CASP8. Induces neuronal apoptosis by interacting with the E2F1 transcription factor and acting synergistically with it to up-regulate pro-apoptotic proteins BCL2L11/BIM and HRK/Dp5. Interacts with TRADD following exposure to UV radiation and induces apoptosis by caspase-dependent JNK activation.
• KEGG Pathway:
  Ribosome (hsa03010)
  Pathogenic Escherichia coli infection (hsa05130)
  Salmonella infection (hsa05132)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Peptide chain elongation (R-HSA-156902)
  SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)
  Viral mRNA Translation (R-HSA-192823)
  Selenocysteine synthesis (R-HSA-2408557)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  Translation initiation complex formation (R-HSA-72649)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  Formation of the ternary complex, and subsequently, the 43S complex (R-HSA-72695)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  Eukaryotic Translation Termination (R-HSA-72764)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)
  SARS-CoV-1 modulates host translation machinery (R-HSA-9735869)
  SARS-CoV-2 modulates host translation machinery (R-HSA-9754678)
  Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) (R-HSA-975956)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Melanoma	DIS1RRCY	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[5]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[6]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[5]
Werner syndrome	DISZY45W	moderate	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]
Asthma	DISW9QNS	Limited	Biomarker	[8]
Osteoarthritis	DIS05URM	Limited	Biomarker	[9]

15 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 Small ribosomal subunit protein uS3 (RPS3).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Small ribosomal subunit protein uS3 (RPS3).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Small ribosomal subunit protein uS3 (RPS3).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Small ribosomal subunit protein uS3 (RPS3).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Small ribosomal subunit protein uS3 (RPS3).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Small ribosomal subunit protein uS3 (RPS3).	[15]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Small ribosomal subunit protein uS3 (RPS3).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Small ribosomal subunit protein uS3 (RPS3).	[17]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Small ribosomal subunit protein uS3 (RPS3).	[17]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Small ribosomal subunit protein uS3 (RPS3).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Small ribosomal subunit protein uS3 (RPS3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Small ribosomal subunit protein uS3 (RPS3).	[22]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Small ribosomal subunit protein uS3 (RPS3).	[23]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Small ribosomal subunit protein uS3 (RPS3).	[24]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Small ribosomal subunit protein uS3 (RPS3).	[25]

4 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 Small ribosomal subunit protein uS3 (RPS3).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Small ribosomal subunit protein uS3 (RPS3).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Small ribosomal subunit protein uS3 (RPS3).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Small ribosomal subunit protein uS3 (RPS3).	[21]

References

• [1] RNF138-mediated ubiquitination of rpS3 is required for resistance of glioblastoma cells to radiation-induced apoptosis.Exp Mol Med. 2018 Jan 26;50(1):e434. doi: 10.1038/emm.2017.247.
• [2] RNA-binding protein RPS3 contributes to hepatocarcinogenesis by post-transcriptionally up-regulating SIRT1.Nucleic Acids Res. 2019 Feb 28;47(4):2011-2028. doi: 10.1093/nar/gky1209.
• [3] RPS3 regulates melanoma cell growth and apoptosis by targeting Cyto C/Ca2+/MICU1 dependent mitochondrial signaling.Oncotarget. 2015 Oct 6;6(30):29614-25. doi: 10.18632/oncotarget.4868.
• [4] A novel TLR4 binding protein, 40S ribosomal protein S3, has potential utility as an adjuvant in a dendritic cell-based vaccine.J Immunother Cancer. 2019 Feb 28;7(1):60. doi: 10.1186/s40425-019-0539-7.
• [5] Ribosomal protein S3 regulates GLI2-mediated osteosarcoma invasion.Cancer Lett. 2015 Jan 28;356(2 Pt B):855-61. doi: 10.1016/j.canlet.2014.10.042. Epub 2014 Nov 11.
• [6] Ribosomal Protein S3 Gene Silencing Protects Against Cigarette Smoke-Induced Acute Lung Injury.Mol Ther Nucleic Acids. 2018 Sep 7;12:370-380. doi: 10.1016/j.omtn.2018.05.027. Epub 2018 Jul 3.
• [7] Proteome-wide identification of WRN-interacting proteins in untreated and nuclease-treated samples.J Proteome Res. 2011 Mar 4;10(3):1216-27. doi: 10.1021/pr100990s. Epub 2011 Feb 16.
• [8] Ribosomal protein S3 gene silencing protects against experimental allergic asthma.Br J Pharmacol. 2017 Apr;174(7):540-552. doi: 10.1111/bph.13717. Epub 2017 Feb 24.
• [9] Annotating Transcriptional Effects of Genetic Variants in Disease-Relevant Tissue: Transcriptome-Wide Allelic Imbalance in Osteoarthritic Cartilage.Arthritis Rheumatol. 2019 Apr;71(4):561-570. doi: 10.1002/art.40748. Epub 2019 Feb 23.
• [10] 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.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. Gene. 2001 Jan 10;262(1-2):207-14. doi: 10.1016/s0378-1119(00)00530-8.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [23] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [24] 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.
• [25] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.