Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT75ACNG)

• DOT Name: Exosome complex component RRP43 (EXOSC8)
• Synonyms: Exosome component 8; Opa-interacting protein 2; OIP-2; Ribosomal RNA-processing protein 43; p9
• Gene Name: EXOSC8
• Related Disease:
  Nervous system disease
  Pontocerebellar hypoplasia
  Pontocerebellar hypoplasia type 1A
  Pontocerebellar hypoplasia, type 1C
  Colorectal carcinoma
  Pontocerebellar hypoplasia type 1
  Pontocerebellar hypoplasia type 1B
  Spinal muscular atrophy
• UniProt ID: EXOS8_HUMAN
• PDB ID: 2NN6; 6D6Q; 6D6R; 6H25
• Pfam ID: PF01138 ; PF03725
• Sequence:
  MAAGFKTVEPLEYYRRFLKENCRPDGRELGEFRTTTVNIGSISTADGSALVKLGNTTVIC
  GVKAEFAAPSTDAPDKGYVVPNVDLPPLCSSRFRSGPPGEEAQVASQFIADVIENSQIIQ
  KEDLCISPGKLVWVLYCDLICLDYDGNILDACTFALLAALKNVQLPEVTINEETALAEVN
  LKKKSYLNIRTHPVATSFAVFDDTLLIVDPTGEEEHLATGTLTIVMDEEGKLCCLHKPGG
  SGLTGAKLQDCMSRAVTRHKEVKKLMDEVIKSMKPK
• 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. EXOSC8 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

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[1]
Pontocerebellar hypoplasia	DISRICMU	Strong	Genetic Variation	[2]
Pontocerebellar hypoplasia type 1A	DIS7X0VS	Strong	GermlineCausalMutation	[1]
Pontocerebellar hypoplasia, type 1C	DISSWARN	Strong	Autosomal recessive	[1]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[3]
Pontocerebellar hypoplasia type 1	DISU1PSQ	Supportive	Autosomal recessive	[1]
Pontocerebellar hypoplasia type 1B	DISZO2HP	Disputed	Biomarker	[4]
Spinal muscular atrophy	DISTLKOB	Limited	Genetic Variation	[5]

17 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 RRP43 (EXOSC8).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Exosome complex component RRP43 (EXOSC8).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Exosome complex component RRP43 (EXOSC8).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Exosome complex component RRP43 (EXOSC8).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Exosome complex component RRP43 (EXOSC8).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Exosome complex component RRP43 (EXOSC8).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Exosome complex component RRP43 (EXOSC8).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Exosome complex component RRP43 (EXOSC8).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Exosome complex component RRP43 (EXOSC8).	[13]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Exosome complex component RRP43 (EXOSC8).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Exosome complex component RRP43 (EXOSC8).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Exosome complex component RRP43 (EXOSC8).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Exosome complex component RRP43 (EXOSC8).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Exosome complex component RRP43 (EXOSC8).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Exosome complex component RRP43 (EXOSC8).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Exosome complex component RRP43 (EXOSC8).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Exosome complex component RRP43 (EXOSC8).	[21]

References

• [1] EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia. Nat Commun. 2014 Jul 3;5:4287. doi: 10.1038/ncomms5287.
• [2] Altered RNA metabolism due to a homozygous RBM7 mutation in a patient with spinal motor neuropathy.Hum Mol Genet. 2016 Jul 15;25(14):2985-2996. doi: 10.1093/hmg/ddw149. Epub 2016 May 18.
• [3] Comprehensive characterization of the rRNA metabolism-related genes in human cancer.Oncogene. 2020 Jan;39(4):786-800. doi: 10.1038/s41388-019-1026-9. Epub 2019 Sep 23.
• [4] The RNA Exosome and Human Disease.Methods Mol Biol. 2020;2062:3-33. doi: 10.1007/978-1-4939-9822-7_1.
• [5] Pontocerebellar hypoplasia type 1 for the neuropediatrician: Genotype-phenotype correlations and diagnostic guidelines based on new cases and overview of the literature.Eur J Paediatr Neurol. 2018 Jul;22(4):674-681. doi: 10.1016/j.ejpn.2018.03.011. Epub 2018 Apr 3.
• [6] 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.
• [7] 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.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] 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.
• [10] 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.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] 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.
• [13] 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.
• [14] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [17] 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.
• [18] 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.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] 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.