Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAC10N6)

• DOT Name: Exosome complex component MTR3 (EXOSC6)
• Synonyms: Exosome component 6; mRNA transport regulator 3 homolog; hMtr3; p11
• Gene Name: EXOSC6
• Related Disease:
  Parkinson disease
  Acute lymphocytic leukaemia
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Childhood acute lymphoblastic leukemia
  Depression
  Hematologic disease
  Hereditary neuropathy with liability to pressure palsies
  Hydrocephalus
  Irritable bowel syndrome
  Malignant soft tissue neoplasm
  Neuroblastoma
  Post-traumatic stress disorder
  Sarcoma
  Smith-Magenis syndrome
  Thyroid gland carcinoma
  Adrenoleukodystrophy
  Neoplasm
  Advanced cancer
  Anxiety
  Anxiety disorder
  Mental disorder
  Schizophrenia
• UniProt ID: EXOS6_HUMAN
• PDB ID: 2NN6; 6D6Q; 6D6R; 6H25
• Pfam ID: PF01138
• Sequence:
  MPGDHRRIRGPEESQPPQLYAADEEEAPGTRDPTRLRPVYARAGLLSQAKGSAYLEAGGT
  KVLCAVSGPRQAEGGERGGGPAGAGGEAPAALRGRLLCDFRRAPFAGRRRRAPPGGCEER
  ELALALQEALEPAVRLGRYPRAQLEVSALLLEDGGSALAAALTAAALALADAGVEMYDLV
  VGCGLSLAPGPAPTWLLDPTRLEEERAAAGLTVALMPVLNQVAGLLGSGEGGLTESWAEA
  VRLGLEGCQRLYPVLQQSLVRAARRRGAAAQP
• 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.
• 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

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Definitive	Altered Expression	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[2]
Depression	DIS3XJ69	Strong	Biomarker	[5]
Hematologic disease	DIS9XD9A	Strong	Altered Expression	[6]
Hereditary neuropathy with liability to pressure palsies	DISY0X1V	Strong	Biomarker	[7]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[8]
Irritable bowel syndrome	DIS27206	Strong	Altered Expression	[9]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Genetic Variation	[10]
Neuroblastoma	DISVZBI4	Strong	Genetic Variation	[3]
Post-traumatic stress disorder	DISHL1EY	Strong	Altered Expression	[11]
Sarcoma	DISZDG3U	Strong	Genetic Variation	[10]
Smith-Magenis syndrome	DISG4G6X	Strong	Biomarker	[7]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[12]
Adrenoleukodystrophy	DISTUD1F	moderate	Altered Expression	[13]
Neoplasm	DISZKGEW	moderate	Biomarker	[12]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[14]
Anxiety	DISIJDBA	Limited	Biomarker	[15]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[15]
Mental disorder	DIS3J5R8	Limited	Biomarker	[11]
Schizophrenia	DISSRV2N	Limited	Altered Expression	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Exosome complex component MTR3 (EXOSC6).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Exosome complex component MTR3 (EXOSC6).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Exosome complex component MTR3 (EXOSC6).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Exosome complex component MTR3 (EXOSC6).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Exosome complex component MTR3 (EXOSC6).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Exosome complex component MTR3 (EXOSC6).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Exosome complex component MTR3 (EXOSC6).	[23]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Exosome complex component MTR3 (EXOSC6).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Exosome complex component MTR3 (EXOSC6).	[25]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Exosome complex component MTR3 (EXOSC6).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Exosome complex component MTR3 (EXOSC6).	[27]

References

• [1] Alterations of p11 in brain tissue and peripheral blood leukocytes in Parkinson's disease.Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2735-2740. doi: 10.1073/pnas.1621218114. Epub 2017 Jan 30.
• [2] Disruption of Annexin II /p11 Interaction Suppresses Leukemia Cell Binding, Homing and Engraftment, and Sensitizes the Leukemia Cells to Chemotherapy.PLoS One. 2015 Oct 14;10(10):e0140564. doi: 10.1371/journal.pone.0140564. eCollection 2015.
• [3] 5-HT1B and other related serotonergic proteins are altered in APPswe mutation. Neurosci Lett. 2015 May 6;594:137-43.
• [4] Synergistic inhibition of breast cancer cell lines with a dual inhibitor of EGFR-HER-2/neu and a Bcl-2 inhibitor.Oncol Rep. 2007 Feb;17(2):465-9.
• [5] IGF-II-Conjugated Nanocarrier for Brain-Targeted Delivery of p11 Gene for Depression.AAPS PharmSciTech. 2019 Jan 7;20(2):50. doi: 10.1208/s12249-018-1206-x.
• [6] Chromosome 12 rearrangement with breakage at the p11 level in hematologic disorders: report of four cases.Cancer Genet Cytogenet. 1985 Feb 15;15(3-4):309-14. doi: 10.1016/0165-4608(85)90175-x.
• [7] Microsatellite mapping of the deletion in patients with hereditary neuropathy with liability to pressure palsies (HNPP): new molecular tools for the study of the region 17p12 --> p11 and for diagnosis.Cytogenet Cell Genet. 1996;72(1):20-5. doi: 10.1159/000134153.
• [8] Impaired neural differentiation and glymphatic CSF flow in the Ccdc39 rat model of neonatal hydrocephalus: genetic interaction with L1cam.Dis Model Mech. 2019 Nov 21;12(11):dmm040972. doi: 10.1242/dmm.040972.
• [9] Alterations in expression of p11 and SERT in mucosal biopsy specimens of patients with irritable bowel syndrome.Gastroenterology. 2007 Jan;132(1):17-25. doi: 10.1053/j.gastro.2006.11.020. Epub 2006 Nov 17.
• [10] Loss of TP53 in sarcomas with 17p12 to approximately p11 gain. A fine-resolution oligonucleotide array comparative genomic hybridization study.Cytogenet Genome Res. 2007;116(3):153-7. doi: 10.1159/000098180.
• [11] P11 (S100A10) as a potential biomarker of psychiatric patients at risk of suicide.J Psychiatr Res. 2011 Apr;45(4):435-41. doi: 10.1016/j.jpsychires.2010.08.012. Epub 2010 Sep 22.
• [12] Peptide P11 suppresses the growth of human thyroid carcinoma by inhibiting the PI3K/AKT/mTOR signaling pathway.Mol Biol Rep. 2019 Jun;46(3):2665-2678. doi: 10.1007/s11033-019-04698-7. Epub 2019 Apr 26.
• [13] Direct effects of alcohol on hepatic fibrinolytic balance: implications for alcoholic liver disease.J Hepatol. 2008 Apr;48(4):614-27. doi: 10.1016/j.jhep.2007.12.015. Epub 2008 Jan 29.
• [14] Selective inhibitor of platelet-activating factor acetylhydrolases 1b2 and 1b3 that impairs cancer cell survival.ACS Chem Biol. 2015 Apr 17;10(4):925-32. doi: 10.1021/cb500893q. Epub 2015 Jan 20.
• [15] P11 Loss-of-Function is Associated with Decreased Cell Proliferation and Neurobehavioral Disorders in Mice.Int J Biol Sci. 2019 May 20;15(7):1383-1395. doi: 10.7150/ijbs.33773. eCollection 2019.
• [16] Levels of the potential biomarker p11 in peripheral blood cells distinguish patients with PTSD from those with other major psychiatric disorders.J Psychiatr Res. 2009 Sep;43(13):1078-85. doi: 10.1016/j.jpsychires.2009.03.010. Epub 2009 Apr 19.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [22] 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.
• [23] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [24] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [25] 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.
• [26] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.