Details of Drug Off-Target (DOT)

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

• DOT Name: Poly polymerase tankyrase-1 (TNKS)
• Synonyms: EC 2.4.2.30; ADP-ribosyltransferase diphtheria toxin-like 5; ARTD5; Poly polymerase 5A; Protein poly-ADP-ribosyltransferase tankyrase-1; EC 2.4.2.-; TNKS-1; TRF1-interacting ankyrin-related ADP-ribose polymerase; Tankyrase I; Tankyrase-1; TANK1
• Gene Name: TNKS
• UniProt ID: TNKS1_HUMAN
• PDB ID: 2RF5 ; 3UDD ; 3UH2 ; 3UH4 ; 4DVI ; 4I9I ; 4K4E ; 4K4F ; 4KRS ; 4LI6 ; 4LI7 ; 4LI8 ; 4MSG ; 4MSK ; 4MT9 ; 4N3R ; 4N4V ; 4OA7 ; 4TOR ; 4TOS ; 4U6A ; 4UUH ; 4UW1 ; 4W5S ; 4W6E ; 5EBT ; 5ECE ; 5ETY ; 5GP7 ; 5JHQ ; 5JTI ; 5JU5 ; 5KNI ; 6QXU ; 6URQ ; 7KKM ; 7KKN ; 7KKO ; 7KKP ; 7KKQ ; 7OCV
• EC Number: 2.4.2.-; 2.4.2.30
• Pfam ID: PF00023 ; PF12796 ; PF13637 ; PF00644 ; PF07647
• Sequence:
  MAASRRSQHHHHHHQQQLQPAPGASAPPPPPPPPLSPGLAPGTTPASPTASGLAPFASPR
  HGLALPEGDGSRDPPDRPRSPDPVDGTSCCSTTSTICTVAAAPVVPAVSTSSAAGVAPNP
  AGSGSNNSPSSSSSPTSSSSSSPSSPGSSLAESPEAAGVSSTAPLGPGAAGPGTGVPAVS
  GALRELLEACRNGDVSRVKRLVDAANVNAKDMAGRKSSPLHFAAGFGRKDVVEHLLQMGA
  NVHARDDGGLIPLHNACSFGHAEVVSLLLCQGADPNARDNWNYTPLHEAAIKGKIDVCIV
  LLQHGADPNIRNTDGKSALDLADPSAKAVLTGEYKKDELLEAARSGNEEKLMALLTPLNV
  NCHASDGRKSTPLHLAAGYNRVRIVQLLLQHGADVHAKDKGGLVPLHNACSYGHYEVTEL
  LLKHGACVNAMDLWQFTPLHEAASKNRVEVCSLLLSHGADPTLVNCHGKSAVDMAPTPEL
  RERLTYEFKGHSLLQAAREADLAKVKKTLALEIINFKQPQSHETALHCAVASLHPKRKQV
  TELLLRKGANVNEKNKDFMTPLHVAAERAHNDVMEVLHKHGAKMNALDTLGQTALHRAAL
  AGHLQTCRLLLSYGSDPSIISLQGFTAAQMGNEAVQQILSESTPIRTSDVDYRLLEASKA
  GDLETVKQLCSSQNVNCRDLEGRHSTPLHFAAGYNRVSVVEYLLHHGADVHAKDKGGLVP
  LHNACSYGHYEVAELLVRHGASVNVADLWKFTPLHEAAAKGKYEICKLLLKHGADPTKKN
  RDGNTPLDLVKEGDTDIQDLLRGDAALLDAAKKGCLARVQKLCTPENINCRDTQGRNSTP
  LHLAAGYNNLEVAEYLLEHGADVNAQDKGGLIPLHNAASYGHVDIAALLIKYNTCVNATD
  KWAFTPLHEAAQKGRTQLCALLLAHGADPTMKNQEGQTPLDLATADDIRALLIDAMPPEA
  LPTCFKPQATVVSASLISPASTPSCLSAASSIDNLTGPLAELAVGGASNAGDGAAGTERK
  EGEVAGLDMNISQFLKSLGLEHLRDIFETEQITLDVLADMGHEELKEIGINAYGHRHKLI
  KGVERLLGGQQGTNPYLTFHCVNQGTILLDLAPEDKEYQSVEEEMQSTIREHRDGGNAGG
  IFNRYNVIRIQKVVNKKLRERFCHRQKEVSEENHNHHNERMLFHGSPFINAIIHKGFDER
  HAYIGGMFGAGIYFAENSSKSNQYVYGIGGGTGCPTHKDRSCYICHRQMLFCRVTLGKSF
  LQFSTMKMAHAPPGHHSVIGRPSVNGLAYAEYVIYRGEQAYPEYLITYQIMKPEAPSQTA
  TAAEQKT
• Function: Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1. Stimulates 26S proteasome activity.
• Tissue Specificity: Ubiquitous; highest levels in testis.
• Reactome Pathway:
  Degradation of AXIN (R-HSA-4641257)
  XAV939 stabilizes AXIN (R-HSA-5545619)
  Ub-specific processing proteases (R-HSA-5689880)
  Regulation of PTEN stability and activity (R-HSA-8948751)
  TCF dependent signaling in response to WNT (R-HSA-201681)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Poly polymerase tankyrase-1 (TNKS) affects the response to substance of Etoposide.	[13]
Mitoxantrone	DMM39BF	Approved	Poly polymerase tankyrase-1 (TNKS) affects the response to substance of Mitoxantrone.	[13]

1 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 Poly polymerase tankyrase-1 (TNKS).	[1]

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 Poly polymerase tankyrase-1 (TNKS).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Poly polymerase tankyrase-1 (TNKS).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Poly polymerase tankyrase-1 (TNKS).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Poly polymerase tankyrase-1 (TNKS).	[5]
Marinol	DM70IK5	Approved	Marinol increases the expression of Poly polymerase tankyrase-1 (TNKS).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Poly polymerase tankyrase-1 (TNKS).	[7]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Poly polymerase tankyrase-1 (TNKS).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Poly polymerase tankyrase-1 (TNKS).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Poly polymerase tankyrase-1 (TNKS).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Poly polymerase tankyrase-1 (TNKS).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PJ34	DMXO6YH	Preclinical	PJ34 affects the binding of Poly polymerase tankyrase-1 (TNKS).	[10]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
• [9] 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.
• [10] Structure of human tankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Feb 1;68(Pt 2):115-8. doi: 10.1107/S1744309111051219. Epub 2012 Jan 21.
• [11] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.