Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH8Z0AL)

• DOT Name: Exosome complex component 10 (EXOSC10)
• Synonyms: EC 3.1.13.-; Autoantigen PM/Scl 2; P100 polymyositis-scleroderma overlap syndrome-associated autoantigen; Polymyositis/scleroderma autoantigen 100 kDa; PM/Scl-100; Polymyositis/scleroderma autoantigen 2
• Gene Name: EXOSC10
• Related Disease:
  High blood pressure
  Idiopathic inflammatory myopathy
  Polymyositis
  Scleroderma
  Skin disease
  Systemic sclerosis
• UniProt ID: EXOSX_HUMAN
• PDB ID: 2CPR; 3SAF; 3SAG; 3SAH; 6D6Q; 6D6R; 7MQA
• EC Number: 3.1.13.-
• Pfam ID: PF01612 ; PF00570 ; PF08066
• Sequence:
  MAPPSTREPRVLSATSATKSDGEMVLPGFPDADSFVKFALGSVVAVTKASGGLPQFGDEY
  DFYRSFPGFQAFCETQGDRLLQCMSRVMQYHGCRSNIKDRSKVTELEDKFDLLVDANDVI
  LERVGILLDEASGVNKNQQPVLPAGLQVPKTVVSSWNRKAAEYGKKAKSETFRLLHAKNI
  IRPQLKFREKIDNSNTPFLPKIFIKPNAQKPLPQALSKERRERPQDRPEDLDVPPALADF
  IHQQRTQQVEQDMFAHPYQYELNHFTPADAVLQKPQPQLYRPIEETPCHFISSLDELVEL
  NEKLLNCQEFAVDLEHHSYRSFLGLTCLMQISTRTEDFIIDTLELRSDMYILNESLTDPA
  IVKVFHGADSDIEWLQKDFGLYVVNMFDTHQAARLLNLGRHSLDHLLKLYCNVDSNKQYQ
  LADWRIRPLPEEMLSYARDDTHYLLYIYDKMRLEMWERGNGQPVQLQVVWQRSRDICLKK
  FIKPIFTDESYLELYRKQKKHLNTQQLTAFQLLFAWRDKTARREDESYGYVLPNHMMLKI
  AEELPKEPQGIIACCNPVPPLVRQQINEMHLLIQQAREMPLLKSEVAAGVKKSGPLPSAE
  RLENVLFGPHDCSHAPPDGYPIIPTSGSVPVQKQASLFPDEKEDNLLGTTCLIATAVITL
  FNEPSAEDSKKGPLTVAQKKAQNIMESFENPFRMFLPSLGHRAPVSQAAKFDPSTKIYEI
  SNRWKLAQVQVQKDSKEAVKKKAAEQTAAREQAKEACKAAAEQAISVRQQVVLENAAKKR
  ERATSDPRTTEQKQEKKRLKISKKPKDPEPPEKEFTPYDYSQSDFKAFAGNSKSKVSSQF
  DPNKQTPSGKKCIAAKKIKQSVGNKSMSFPTGKSDRGFRYNWPQR
• Function: 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. 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. 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. EXOSC10 is required for nucleolar localization of C1D and probably mediates the association of MTREX, C1D and MPHOSPH6 with the RNA exosome involved in the maturation of 5.8S rRNA. Plays a role in the recruitment of replication protein A complex (RPA) and RAD51 to DNA double-strand breaks caused by irradiation, contributing to DNA repair by homologous recombination. Regulates levels of damage-induced RNAs in order to prevent DNA-RNA hybrid formation at DNA double-strand breaks and limit DNA end resection after damage. Plays a role in oocyte development, maturation and survival. Required for normal testis development and mitotic division of spermatogonia. Plays a role in proper embryo development. Required for global protein translation. Required for cell proliferation. Regulates metabolism of C9orf72-derived repeat RNA that can be translated into toxic dipeptide repeat proteins.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway: Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
High blood pressure	DISY2OHH	Strong	Biomarker	[1]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Biomarker	[2]
Polymyositis	DIS5DHFP	Strong	Biomarker	[3]
Scleroderma	DISVQ342	Strong	Genetic Variation	[4]
Skin disease	DISDW8R6	Strong	Biomarker	[1]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Exosome complex component 10 (EXOSC10).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Exosome complex component 10 (EXOSC10).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Exosome complex component 10 (EXOSC10).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Exosome complex component 10 (EXOSC10).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Exosome complex component 10 (EXOSC10).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Exosome complex component 10 (EXOSC10).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Exosome complex component 10 (EXOSC10).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Exosome complex component 10 (EXOSC10).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Exosome complex component 10 (EXOSC10).	[17]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the metabolism of Exosome complex component 10 (EXOSC10).	[13]

2 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 10 (EXOSC10).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Exosome complex component 10 (EXOSC10).	[15]

References

• [1] The clinical relevance of autoantibodies in scleroderma.Arthritis Res Ther. 2003;5(2):80-93. doi: 10.1186/ar628. Epub 2003 Feb 12.
• [2] An update on the immunogenetics of idiopathic inflammatory myopathies: major histocompatibility complex and beyond.Curr Opin Rheumatol. 2009 Nov;21(6):588-93. doi: 10.1097/BOR.0b013e3283315a22.
• [3] Novel aspects of autoantibodies to the PM/Scl complex: clinical, genetic and diagnostic insights.Autoimmun Rev. 2007 Aug;6(7):432-7. doi: 10.1016/j.autrev.2007.01.013. Epub 2007 Feb 20.
• [4] C1D is a major autoantibody target in patients with the polymyositis-scleroderma overlap syndrome.Arthritis Rheum. 2007 Jul;56(7):2449-54. doi: 10.1002/art.22710.
• [5] Concurrent anti-PM-Scl antibody-associated systemic sclerosis and inclusion body myositis - report of two cases and review of the literature.Semin Arthritis Rheum. 2020 Jun;50(3):498-502. doi: 10.1016/j.semarthrit.2019.11.008. Epub 2019 Nov 16.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [10] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [11] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [12] 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.
• [13] The RNA exosome component hRrp6 is a target for 5-fluorouracil in human cells. Mol Cancer Res. 2008 Jun;6(6):990-5. doi: 10.1158/1541-7786.MCR-07-2217.
• [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] 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] 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.