Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG4TICP)

• DOT Name: Exosome complex component RRP41 (EXOSC4)
• Synonyms: Exosome component 4; Ribosomal RNA-processing protein 41; p12A
• Gene Name: EXOSC4
• Related Disease:
  Colorectal carcinoma
  Non-insulin dependent diabetes
  Obesity
• UniProt ID: EXOS4_HUMAN
• PDB ID: 2NN6; 6D6Q; 6D6R; 6H25
• Pfam ID: PF01138 ; PF03725
• Sequence:
  MAGLELLSDQGYRVDGRRAGELRKIQARMGVFAQADGSAYIEQGNTKALAVVYGPHEIRG
  SRARALPDRALVNCQYSSATFSTGERKRRPHGDRKSCEMGLQLRQTFEAAILTQLHPRSQ
  IDIYVQVLQADGGTYAACVNAATLAVLDAGIPMRDFVCACSAGFVDGTALADLSHVEEAA
  GGPQLALALLPASGQIALLEMDARLHEDHLERVLEAAAQAARDVHTLLDRVVRQHVREAS
  ILLGD
• 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. EXOSC4 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[2]
Obesity	DIS47Y1K	Strong	Genetic Variation	[3]

16 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 RRP41 (EXOSC4).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Exosome complex component RRP41 (EXOSC4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Exosome complex component RRP41 (EXOSC4).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Exosome complex component RRP41 (EXOSC4).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Exosome complex component RRP41 (EXOSC4).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Exosome complex component RRP41 (EXOSC4).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Exosome complex component RRP41 (EXOSC4).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Exosome complex component RRP41 (EXOSC4).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Exosome complex component RRP41 (EXOSC4).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Exosome complex component RRP41 (EXOSC4).	[13]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Exosome complex component RRP41 (EXOSC4).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Exosome complex component RRP41 (EXOSC4).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Exosome complex component RRP41 (EXOSC4).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Exosome complex component RRP41 (EXOSC4).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Exosome complex component RRP41 (EXOSC4).	[16]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Exosome complex component RRP41 (EXOSC4).	[17]

References

• [1] EXOSC4 functions as a potential oncogene in development and progression of colorectal cancer.Mol Carcinog. 2018 Dec;57(12):1780-1791. doi: 10.1002/mc.22896. Epub 2018 Sep 21.
• [2] Altered expression of WFS1 and NOTCH2 genes associated with diabetic nephropathy in T2DM patients.Diabetes Res Clin Pract. 2018 Jun;140:304-313. doi: 10.1016/j.diabres.2018.03.053. Epub 2018 Apr 4.
• [3] Genome-wide screen of DNA methylation identifies novel markers in childhood obesity.Gene. 2015 Jul 15;566(1):74-83. doi: 10.1016/j.gene.2015.04.032. Epub 2015 Apr 12.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [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] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [14] 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.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] 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.