Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6ZMFYF)

• DOT Name: THAP domain-containing protein 5 (THAP5)
• Gene Name: THAP5
• Related Disease:
  Cardiac disease
  Coronary heart disease
  Myocardial infarction
• UniProt ID: THAP5_HUMAN
• Pfam ID: PF05485
• Sequence:
  MPRYCAAICCKNRRGRNNKDRKLSFYPFPLHDKERLEKWLKNMKRDSWVPSKYQFLCSDH
  FTPDSLDIRWGIRYLKQTAVPTIFSLPEDNQGKDPSKKKSQKKNLEDEKEVCPKAKSEES
  FVLNETKKNIVNTDVPHQHPELLHSSSLVKPPAPKTGSIQNNMLTLNLVKQHTGKPESTL
  ETSVNQDTGRGGFHTCFENLNSTTITLTTSNSESIHQSLETQEVLEVTTSHLANPNFTSN
  SMEIKSAQENPFLFSTINQTVEELNTNKESVIAIFVPAENSKPSVNSFISAQKETTEMED
  TDIEDSLYKDVDYGTEVLQIEHSYCRQDINKEHLWQKVSKLHSKITLLELKEQQTLGRLK
  SLEALIRQLKQENWLSEENVKIIENHFTTYEVTMI
• Function: Has sequence-specific DNA-binding activity and can function as transcriptional repressor (in vitro). May be a regulator of cell cycle: THAP5 overexpression in human cell lines causes cell cycle arrest at G2/M phase.
• Tissue Specificity: Detected in heart . Detected in brain and muscle (at protein level) . Highly expressed in the heart. Also found in brain and skeletal muscle .

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac disease	DISVO1I5	Strong	Altered Expression	[1]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[2]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of THAP domain-containing protein 5 (THAP5).	[3]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of THAP domain-containing protein 5 (THAP5).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of THAP domain-containing protein 5 (THAP5).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of THAP domain-containing protein 5 (THAP5).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of THAP domain-containing protein 5 (THAP5).	[2]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of THAP domain-containing protein 5 (THAP5).	[7]

References

• [1] THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death.Am J Physiol Heart Circ Physiol. 2009 Aug;297(2):H643-53. doi: 10.1152/ajpheart.00234.2009. Epub 2009 Jun 5.
• [2] THAP5 is a DNA-binding transcriptional repressor that is regulated in melanoma cells during DNA damage-induced cell death. Biochem Biophys Res Commun. 2011 Jan 7;404(1):195-200. doi: 10.1016/j.bbrc.2010.11.092. Epub 2010 Nov 24.
• [3] 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.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] 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.
• [6] THAP5 is a DNA-binding transcriptional repressor that is regulated in melanoma cells during DNA damage-induced cell death. Biochem Biophys Res Commun. 2011 Jan 7;404(1):195-200. doi: 10.1016/j.bbrc.2010.11.092. Epub 2010 Nov 24.
• [7] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [8] 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.