Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN6NVKL)

• DOT Name: Exosome complex component RRP4 (EXOSC2)
• Synonyms: Exosome component 2; Ribosomal RNA-processing protein 4
• Gene Name: EXOSC2
• Related Disease:
  Retinitis pigmentosa
  Liver cancer
  Precancerous condition
  Premature aging syndrome
  Retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome
• UniProt ID: EXOS2_HUMAN
• PDB ID: 2NN6; 6D6Q; 6D6R; 6H25
• Pfam ID: PF14382 ; PF15985 ; PF21266
• Sequence:
  MAMEMRLPVARKPLSERLGRDTKKHLVVPGDTITTDTGFMRGHGTYMGEEKLIASVAGSV
  ERVNKLICVKALKTRYIGEVGDIVVGRITEVQQKRWKVETNSRLDSVLLLSSMNLPGGEL
  RRRSAEDELAMRGFLQEGDLISAEVQAVFSDGAVSLHTRSLKYGKLGQGVLVQVSPSLVK
  RQKTHFHDLPCGASVILGNNGFIWIYPTPEHKEEEAGGFIANLEPVSLADREVISRLRNC
  IISLVTQRMMLYDTSILYCYEASLPHQIKDILKPEIMEEIVMETRQRLLEQEG
• 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. EXOSC2 as peripheral part of the Exo-9 complex stabilizes the hexameric ring of RNase PH-domain subunits through contacts with EXOSC4 and EXOSC7.
• 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

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Retinitis pigmentosa	DISCGPY8	Definitive	Genetic Variation	[1]
Liver cancer	DISDE4BI	Strong	Biomarker	[2]
Precancerous condition	DISV06FL	Strong	Biomarker	[2]
Premature aging syndrome	DIS51AGT	Strong	Genetic Variation	[3]
Retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome	DIS15KFI	Strong	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Exosome complex component RRP4 (EXOSC2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Exosome complex component RRP4 (EXOSC2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Exosome complex component RRP4 (EXOSC2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Exosome complex component RRP4 (EXOSC2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Exosome complex component RRP4 (EXOSC2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Exosome complex component RRP4 (EXOSC2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Exosome complex component RRP4 (EXOSC2).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Exosome complex component RRP4 (EXOSC2).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Exosome complex component RRP4 (EXOSC2).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Exosome complex component RRP4 (EXOSC2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Exosome complex component RRP4 (EXOSC2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Exosome complex component RRP4 (EXOSC2).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Exosome complex component RRP4 (EXOSC2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Exosome complex component RRP4 (EXOSC2).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Exosome complex component RRP4 (EXOSC2).	[20]

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 affects the methylation of Exosome complex component RRP4 (EXOSC2).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Exosome complex component RRP4 (EXOSC2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Exosome complex component RRP4 (EXOSC2).	[18]

References

• [1] The RNA Exosome and Human Disease.Methods Mol Biol. 2020;2062:3-33. doi: 10.1007/978-1-4939-9822-7_1.
• [2] Multiple genes exhibit phenobarbital-induced constitutive active/androstane receptor-mediated DNA methylation changes during liver tumorigenesis and in liver tumors.Toxicol Sci. 2009 Apr;108(2):273-89. doi: 10.1093/toxsci/kfp031. Epub 2009 Feb 20.
• [3] Mutations in EXOSC2 are associated with a novel syndrome characterised by retinitis pigmentosa, progressive hearing loss, premature ageing, short stature, mild intellectual disability and distinctive gestalt. J Med Genet. 2016 Jun;53(6):419-25. doi: 10.1136/jmedgenet-2015-103511. Epub 2016 Feb 3.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [8] 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.
• [9] 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.
• [10] Gene expression profile of multiple myeloma cell line treated by arsenic trioxide. J Huazhong Univ Sci Technolog Med Sci. 2007 Dec;27(6):646-9. doi: 10.1007/s11596-007-0606-z.
• [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] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] DON shares a similar mode of action as the ribotoxic stress inducer anisomycin while TBTO shares ER stress patterns with the ER stress inducer thapsigargin based on comparative gene expression profiling in Jurkat T cells. Toxicol Lett. 2014 Jan 30;224(3):395-406. doi: 10.1016/j.toxlet.2013.11.005. Epub 2013 Nov 15.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.