Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFKB37F)

• DOT Name: Exosome complex component RRP45 (EXOSC9)
• Synonyms: Autoantigen PM/Scl 1; Exosome component 9; P75 polymyositis-scleroderma overlap syndrome-associated autoantigen; Polymyositis/scleroderma autoantigen 1; Polymyositis/scleroderma autoantigen 75 kDa; PM/Scl-75
• Gene Name: EXOSC9
• Related Disease:
  Polymyositis
  Pontocerebellar hypoplasia type 1A
  Pontocerebellar hypoplasia, type 1D
  Respiratory failure
  Lactic acidosis
  Pontocerebellar hypoplasia type 1
• UniProt ID: EXOS9_HUMAN
• PDB ID: 2NN6; 6D6Q; 6D6R; 6H25
• Pfam ID: PF01138 ; PF03725
• Sequence:
  MKETPLSNCERRFLLRAIEEKKRLDGRQTYDYRNIRISFGTDYGCCIVELGKTRVLGQVS
  CELVSPKLNRATEGILFFNLELSQMAAPAFEPGRQSDLLVKLNRLMERCLRNSKCIDTES
  LCVVAGEKVWQIRVDLHLLNHDGNIIDAASIAAIVALCHFRRPDVSVQGDEVTLYTPEER
  DPVPLSIHHMPICVSFAFFQQGTYLLVDPNEREERVMDGLLVIAMNKHREICTIQSSGGI
  MLLKDQVLRCSKIAGVKVAEITELILKALENDQKVRKEGGKFGFAESIANQRITAFKMEK
  APIDTSDVEEKAEEIIAEAEPPSEVVSTPVLWTPGTAQIGEGVENSWGDLEDSEKEDDEG
  GGDQAIILDGIKMDTGVEVSDIGSQDAPIILSDSEEEEMIILEPDKNPKKIRTQTTSAKQ
  EKAPSKKPVKRRKKKRAAN
• Function: Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3' untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC9 binds to ARE-containing RNAs.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway:
  mRNA decay by 3' to 5' exoribonuclease (R-HSA-429958)
  Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA (R-HSA-450385)
  Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA (R-HSA-450513)
  KSRP (KHSRP) binds and destabilizes mRNA (R-HSA-450604)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  ATF4 activates genes in response to endoplasmic reticulum stress (R-HSA-380994)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Polymyositis	DIS5DHFP	Strong	Biomarker	[1]
Pontocerebellar hypoplasia type 1A	DIS7X0VS	Strong	GermlineCausalMutation	[2]
Pontocerebellar hypoplasia, type 1D	DIS1DDS3	Strong	Autosomal recessive	[2]
Respiratory failure	DISVMYJO	Strong	Genetic Variation	[3]
Lactic acidosis	DISZI1ZK	moderate	Genetic Variation	[3]
Pontocerebellar hypoplasia type 1	DISU1PSQ	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Exosome complex component RRP45 (EXOSC9) affects the response to substance of Vinblastine.	[18]

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 Exosome complex component RRP45 (EXOSC9).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Exosome complex component RRP45 (EXOSC9).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Exosome complex component RRP45 (EXOSC9).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Exosome complex component RRP45 (EXOSC9).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Exosome complex component RRP45 (EXOSC9).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Exosome complex component RRP45 (EXOSC9).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Exosome complex component RRP45 (EXOSC9).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Exosome complex component RRP45 (EXOSC9).	[10]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Exosome complex component RRP45 (EXOSC9).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Exosome complex component RRP45 (EXOSC9).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Exosome complex component RRP45 (EXOSC9).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Exosome complex component RRP45 (EXOSC9).	[16]

3 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 Exosome complex component RRP45 (EXOSC9).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Exosome complex component RRP45 (EXOSC9).	[14]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Exosome complex component RRP45 (EXOSC9).	[17]

References

• [1] PM-Scl-75 is the main autoantigen in patients with the polymyositis/scleroderma overlap syndrome.Arthritis Rheum. 2004 Feb;50(2):565-9. doi: 10.1002/art.20056.
• [2] Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy. Am J Hum Genet. 2018 May 3;102(5):858-873. doi: 10.1016/j.ajhg.2018.03.011.
• [3] Expanded PCH1D phenotype linked to EXOSC9 mutation.Eur J Med Genet. 2020 Jan;63(1):103622. doi: 10.1016/j.ejmg.2019.01.012. Epub 2019 Jan 25.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] 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.
• [11] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.