Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTADUQ7H)

• DOT Name: Exosome complex component RRP46 (EXOSC5)
• Synonyms: Chronic myelogenous leukemia tumor antigen 28; Exosome component 5; Ribosomal RNA-processing protein 46; p12B
• Gene Name: EXOSC5
• Related Disease:
  Acute myelogenous leukaemia
  Cerebellar ataxia, brain abnormalities, and cardiac conduction defects
  Colorectal carcinoma
  Gastric cancer
  Gastric neoplasm
  Hepatitis B virus infection
  Hereditary diffuse gastric adenocarcinoma
  Testicular cancer
  Advanced cancer
  Neoplasm
  leukaemia
  Leukemia
• UniProt ID: EXOS5_HUMAN
• PDB ID: 2NN6; 6D6Q; 6D6R; 6H25
• Pfam ID: PF01138 ; PF03725
• Sequence:
  MEEETHTDAKIRAENGTGSSPRGPGCSLRHFACEQNLLSRPDGSASFLQGDTSVLAGVYG
  PAEVKVSKEIFNKATLEVILRPKIGLPGVAEKSRERLIRNTCEAVVLGTLHPRTSITVVL
  QVVSDAGSLLACCLNAACMALVDAGVPMRALFCGVACALDSDGTLVLDPTSKQEKEARAV
  LTFALDSVERKLLMSSTKGLYSDTELQQCLAAAQAASQHVFRFYRESLQRRYSKS
• 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. In vitro, EXOSC5 does not bind or digest single-stranded RNA and binds to double-stranded DNA without detectable DNase activity.
• Tissue Specificity: Highly expressed in a variety of hematopoietic and epithelial tumor cell lines, but not in normal hematopoietic tissues or other normal tissue, with the exception of testis.
• 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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Cerebellar ataxia, brain abnormalities, and cardiac conduction defects	DIS3O56R	Strong	Autosomal recessive	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[5]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[4]
Testicular cancer	DIS6HNYO	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Neoplasm	DISZKGEW	moderate	Biomarker	[6]
leukaemia	DISS7D1V	Limited	Altered Expression	[1]
Leukemia	DISNAKFL	Limited	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Exosome complex component RRP46 (EXOSC5).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Exosome complex component RRP46 (EXOSC5).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Exosome complex component RRP46 (EXOSC5).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Exosome complex component RRP46 (EXOSC5).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Exosome complex component RRP46 (EXOSC5).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Exosome complex component RRP46 (EXOSC5).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Exosome complex component RRP46 (EXOSC5).	[11]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Exosome complex component RRP46 (EXOSC5).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Exosome complex component RRP46 (EXOSC5).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Exosome complex component RRP46 (EXOSC5).	[17]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Exosome complex component RRP46 (EXOSC5).	[18]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Exosome complex component RRP46 (EXOSC5).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Exosome complex component RRP46 (EXOSC5).	[16]

References

• [1] Graft-versus-leukemia target antigens in chronic myelogenous leukemia are expressed on myeloid progenitor cells.Clin Cancer Res. 2005 Jun 15;11(12):4504-11. doi: 10.1158/1078-0432.CCR-05-0036.
• [2] Genetics of intellectual disability in consanguineous families. Mol Psychiatry. 2019 Jul;24(7):1027-1039. doi: 10.1038/s41380-017-0012-2. Epub 2018 Jan 4.
• [3] EXOSC5 as a Novel Prognostic Marker Promotes Proliferation of Colorectal Cancer via Activating the ERK and AKT Pathways.Front Oncol. 2019 Jul 18;9:643. doi: 10.3389/fonc.2019.00643. eCollection 2019.
• [4] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [5] Peroxiredoxin 1, a Novel HBx-Interacting Protein, Interacts with Exosome Component 5 and Negatively Regulates Hepatitis B Virus (HBV) Propagation through Degradation of HBV RNA.J Virol. 2019 Mar 5;93(6):e02203-18. doi: 10.1128/JVI.02203-18. Print 2019 Mar 15.
• [6] Identification of a new HLA-A*0201-restricted cytotoxic T lymphocyte epitope from CML28.Cancer Immunol Immunother. 2006 Dec;55(12):1575-83. doi: 10.1007/s00262-006-0152-8. Epub 2006 Mar 14.
• [7] 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.
• [8] 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.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [12] 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.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [18] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.