Details of Drug Off-Target (DOT)

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

• DOT Name: Ataxin-3 (ATXN3)
• Synonyms: EC 3.4.19.12; Machado-Joseph disease protein 1; Spinocerebellar ataxia type 3 protein
• Gene Name: ATXN3
• Related Disease:
  Spinocerebellar ataxia type 3
  Machado-Joseph disease type 1
  Machado-Joseph disease type 2
  Machado-Joseph disease type 3
• UniProt ID: ATX3_HUMAN
• PDB ID: 1YZB; 2AGA; 2DOS; 2JRI; 2KLZ; 4WTH; 4YS9
• EC Number: 3.4.19.12
• Pfam ID: PF02099 ; PF16619 ; PF02809
• Sequence:
  MESIFHEKQEGSLCAQHCLNNLLQGEYFSPVELSSIAHQLDEEERMRMAEGGVTSEDYRT
  FLQQPSGNMDDSGFFSIQVISNALKVWGLELILFNSPEYQRLRIDPINERSFICNYKEHW
  FTVRKLGKQWFNLNSLLTGPELISDTYLALFLAQLQQEGYSIFVVKGDLPDCEADQLLQM
  IRVQQMHRPKLIGEELAQLKEQRVHKTDLERVLEANDGSGMLDEDEEDLQRALALSRQEI
  DMEDEEADLRRAIQLSMQGSSRNISQDMTQTSGTNLTSEELRKRREAYFEKQQQKQQQQQ
  QQQQQGDLSGQSSHPCERPATSSGALGSDLGDAMSEEDMLQAAVTMSLETVRNDLKTEGK
  K
• Function: Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates. Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins. Involved in degradation of misfolded chaperone substrates via its interaction with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, and restricts the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Interacts with key regulators of transcription and represses transcription: acts as a histone-binding protein that regulates transcription. Acts as a negative regulator of mTORC1 signaling in response to amino acid deprivation by mediating deubiquitination of RHEB, thereby promoting RHEB inactivation by the TSC-TBC complex. Regulates autophagy via the deubiquitination of 'Lys-402' of BECN1 leading to the stabilization of BECN1.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  Josephin domain DUBs (R-HSA-5689877)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spinocerebellar ataxia type 3	DISQBQID	Definitive	Autosomal dominant	[1]
Machado-Joseph disease type 1	DISL5OAW	Supportive	Autosomal dominant	[2]
Machado-Joseph disease type 2	DIS2DESR	Supportive	Autosomal dominant	[2]
Machado-Joseph disease type 3	DISWZ7GY	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Disulfiram	DMCL2OK	Phase 2 Trial	Ataxin-3 (ATXN3) increases the response to substance of Disulfiram.	[19]

15 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 Ataxin-3 (ATXN3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ataxin-3 (ATXN3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ataxin-3 (ATXN3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ataxin-3 (ATXN3).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ataxin-3 (ATXN3).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Ataxin-3 (ATXN3).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ataxin-3 (ATXN3).	[9]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Ataxin-3 (ATXN3).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Ataxin-3 (ATXN3).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ataxin-3 (ATXN3).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ataxin-3 (ATXN3).	[15]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Ataxin-3 (ATXN3).	[16]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Ataxin-3 (ATXN3).	[16]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Ataxin-3 (ATXN3).	[17]
L-Serine	DM6WPIS	Investigative	L-Serine increases the expression of Ataxin-3 (ATXN3).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Aluminium	DM6ECN9	Approved	Aluminium affects the folding of Ataxin-3 (ATXN3).	[11]

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 increases the methylation of Ataxin-3 (ATXN3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ataxin-3 (ATXN3).	[14]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] 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.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [11] Destabilization of non-pathological variants of ataxin-3 by metal ions results in aggregation/fibrillogenesis. Int J Biochem Cell Biol. 2007;39(5):966-77. doi: 10.1016/j.biocel.2007.01.012. Epub 2007 Jan 20.
• [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] 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.
• [14] 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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.
• [17] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.
• [18] Mechanisms of L-Serine Neuroprotection in vitro Include ER Proteostasis Regulation. Neurotox Res. 2018 Jan;33(1):123-132. doi: 10.1007/s12640-017-9829-3. Epub 2017 Nov 2.
• [19] Disulfiram facilitates ataxin-3 nuclear translocation and potentiates the cytotoxicity in a cell model of SCA3. J Toxicol Sci. 2019;44(8):535-542. doi: 10.2131/jts.44.535.