Details of Drug Off-Target (DOT)

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

• DOT Name: THAP domain-containing protein 1 (THAP1)
• Gene Name: THAP1
• Related Disease:
  Thyroid gland papillary carcinoma
  Focal dystonia
  Laryngeal disorder
  Paroxysmal dystonia
  T-cell acute lymphoblastic leukaemia
  Torsion dystonia 6
  X-linked dystonia-parkinsonism
  Bjornstad syndrome
  Early-onset generalized limb-onset dystonia
  Movement disorder
  Segmental dystonia
  Parkinson disease
• UniProt ID: THAP1_HUMAN
• PDB ID: 2JTG; 2KO0; 2L1G
• Pfam ID: PF05485
• Sequence:
  MVQSCSAYGCKNRYDKDKPVSFHKFPLTRPSLCKEWEAAVRRKNFKPTKYSSICSEHFTP
  DCFKRECNNKLLKENAVPTIFLCTEPHDKKEDLLEPQEQLPPPPLPPPVSQVDAAIGLLM
  PPLQTPVNLSVFCDHNYTVEDTMHQRKRIHQLEQQVEKLRKKLKTAQQRCRRQERQLEKL
  KEVVHFQKEKDDVSERGYVILPNDYFEIVEVPA
• Function: DNA-binding transcription regulator that regulates endothelial cell proliferation and G1/S cell-cycle progression. Specifically binds the 5'-[AT]NTNN[GT]GGCA[AGT]-3' core DNA sequence and acts by modulating expression of pRB-E2F cell-cycle target genes, including RRM1. Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. May also have pro-apoptotic activity by potentiating both serum-withdrawal and TNF-induced apoptosis.
• Tissue Specificity: Highly expressed in heart, skeletal muscle, kidney and liver. Weaker expression in brain and placenta.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Biomarker	[1]
Focal dystonia	DIS26D7O	Strong	Genetic Variation	[2]
Laryngeal disorder	DISDKUQO	Strong	Genetic Variation	[3]
Paroxysmal dystonia	DISV0MSQ	Strong	Biomarker	[4]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[5]
Torsion dystonia 6	DIS2N5V6	Strong	Autosomal dominant	[6]
X-linked dystonia-parkinsonism	DIS5TT9O	Strong	Altered Expression	[7]
Bjornstad syndrome	DISO267N	moderate	Biomarker	[8]
Early-onset generalized limb-onset dystonia	DISDY57E	moderate	Biomarker	[9]
Movement disorder	DISOJJ2D	moderate	Genetic Variation	[10]
Segmental dystonia	DISOACMU	moderate	Genetic Variation	[11]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[12]

10 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 THAP domain-containing protein 1 (THAP1).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of THAP domain-containing protein 1 (THAP1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of THAP domain-containing protein 1 (THAP1).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of THAP domain-containing protein 1 (THAP1).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of THAP domain-containing protein 1 (THAP1).	[17]
Marinol	DM70IK5	Approved	Marinol decreases the expression of THAP domain-containing protein 1 (THAP1).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of THAP domain-containing protein 1 (THAP1).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of THAP domain-containing protein 1 (THAP1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of THAP domain-containing protein 1 (THAP1).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of THAP domain-containing protein 1 (THAP1).	[23]

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 THAP domain-containing protein 1 (THAP1).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the methylation of THAP domain-containing protein 1 (THAP1).	[24]

References

• [1] Identification of differentiated functional modules in papillary thyroid carcinoma by analyzing differential networks.J Cancer Res Ther. 2018 Dec;14(Supplement):S969-S974. doi: 10.4103/jcrt.JCRT_730_16.
• [2] Lack of association between TOR1A and THAP1 mutations and sporadic adult-onset primary focal dystonia in a Chinese population.Clin Neurol Neurosurg. 2016 Mar;142:26-30. doi: 10.1016/j.clineuro.2016.01.018. Epub 2016 Jan 12.
• [3] THAP1 mutations (DYT6) are an additional cause of early-onset dystonia.Neurology. 2010 Mar 9;74(10):846-50. doi: 10.1212/WNL.0b013e3181d5276d.
• [4] Mutations in GNAL cause primary torsion dystonia. Nat Genet. 2013 Jan;45(1):88-92. doi: 10.1038/ng.2496. Epub 2012 Dec 9.
• [5] A novel long non-coding RNA T-ALL-R-LncR1 knockdown and Par-4 cooperate to induce cellular apoptosis in T-cell acute lymphoblastic leukemia cells.Leuk Lymphoma. 2014 Jun;55(6):1373-82. doi: 10.3109/10428194.2013.829574. Epub 2013 Aug 28.
• [6] 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.
• [7] DYT6 dystonia: review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene.Hum Mutat. 2011 Nov;32(11):1213-24. doi: 10.1002/humu.21564. Epub 2011 Sep 15.
• [8] Screening of Brazilian families with primary dystonia reveals a novel THAP1 mutation and a de novo TOR1A GAG deletion.Mov Disord. 2010 Dec 15;25(16):2854-7. doi: 10.1002/mds.23133.
• [9] Inherited isolated dystonia: clinical genetics and gene function.Neurotherapeutics. 2014 Oct;11(4):807-16. doi: 10.1007/s13311-014-0297-7.
• [10] Intracranial calcifications and dystonia associated with a novel deletion of chromosome 8p11.2 encompassing SLC20A2 and THAP1.BMJ Case Rep. 2019 May 27;12(5):e228782. doi: 10.1136/bcr-2018-228782.
• [11] Long-term effect on dystonia after pallidal deep brain stimulation (DBS) in three members of a family with a THAP1 mutation.J Neurol. 2015 Dec;262(12):2739-44. doi: 10.1007/s00415-015-7908-z. Epub 2015 Oct 20.
• [12] Novel THAP1 sequence variants in primary dystonia.Neurology. 2010 Jan 19;74(3):229-38. doi: 10.1212/WNL.0b013e3181ca00ca.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [19] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.