Details of Drug Off-Target (DOT)

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

• DOT Name: Protein mono-ADP-ribosyltransferase PARP14 (PARP14)
• Synonyms: EC 2.4.2.-; ADP-ribosyltransferase diphtheria toxin-like 8; ARTD8; B aggressive lymphoma protein 2; Poly polymerase 14; PARP-14
• Gene Name: PARP14
• Related Disease:
  Advanced cancer
  Glucagonoma
  Major depressive disorder
  Metastatic prostate carcinoma
  Plasma cell myeloma
  Skin disease
  B-cell lymphoma
  Neoplasm
  Pancreatic cancer
  Hepatocellular carcinoma
  Asthma
• UniProt ID: PAR14_HUMAN
• PDB ID: 3GOY ; 3Q6Z ; 3Q71 ; 3SE2 ; 3SMI ; 3SMJ ; 3VFQ ; 4ABK ; 4ABL ; 4D86 ; 4F1L ; 4F1Q ; 4PY4 ; 5LXP ; 5LYH ; 5NQE ; 5O2D ; 5QHT ; 5QHU ; 5QHV ; 5QHW ; 5QHX ; 5QHY ; 5QHZ ; 5QI0 ; 5QI1 ; 5QI2 ; 5QI3 ; 5QI4 ; 5QI5 ; 5QI6 ; 5QI7 ; 5QI8 ; 5QI9 ; 5QIA ; 5V7T ; 5V7W ; 6FYM ; 6FZM ; 6G0W ; 6WE2 ; 6WE3 ; 6WE4 ; 7D2C ; 7L9Y ; 7LUN ; 7R3L
• EC Number: 2.4.2.-
• Pfam ID: PF01661 ; PF00644 ; PF02825
• Sequence:
  MAVPGSFPLLVEGSWGPDPPKNLNTKLQMYFQSPKRSGGGECEVRQDPRSPSRFLVFFYP
  EDVRQKVLERKNHELVWQGKGTFKLTVQLPATPDEIDHVFEEELLTKESKTKEDVKEPDV
  SEELDTKLPLDGGLDKMEDIPEECENISSLVAFENLKANVTDIMLILLVENISGLSNDDF
  QVEIIRDFDVAVVTFQKHIDTIRFVDDCTKHHSIKQLQLSPRLLEVTNTIRVENLPPGAD
  DYSLKLFFENPYNGGGRVANVEYFPEESSALIEFFDRKVLDTIMATKLDFNKMPLSVFPY
  YASLGTALYGKEKPLIKLPAPFEESLDLPLWKFLQKKNHLIEEINDEMRRCHCELTWSQL
  SGKVTIRPAATLVNEGRPRIKTWQADTSTTLSSIRSKYKVNPIKVDPTMWDTIKNDVKDD
  RILIEFDTLKEMVILAGKSEDVQSIEVQVRELIESTTQKIKREEQSLKEKMIISPGRYFL
  LCHSSLLDHLLTECPEIEICYDRVTQHLCLKGPSADVYKAKCEIQEKVYTMAQKNIQVSP
  EIFQFLQQVNWKEFSKCLFIAQKILALYELEGTTVLLTSCSSEALLEAEKQMLSALNYKR
  IEVENKEVLHGKKWKGLTHNLLKKQNSSPNTVIINELTSETTAEVIITGCVKEVNETYKL
  LFNFVEQNMKIERLVEVKPSLVIDYLKTEKKLFWPKIKKVNVQVSFNPENKQKGILLTGS
  KTEVLKAVDIVKQVWDSVCVKSVHTDKPGAKQFFQDKARFYQSEIKRLFGCYIELQENEV
  MKEGGSPAGQKCFSRTVLAPGVVLIVQQGDLARLPVDVVVNASNEDLKHYGGLAAALSKA
  AGPELQADCDQIVKREGRLLPGNATISKAGKLPYHHVIHAVGPRWSGYEAPRCVYLLRRA
  VQLSLCLAEKYKYRSIAIPAISSGVFGFPLGRCVETIVSAIKENFQFKKDGHCLKEIYLV
  DVSEKTVEAFAEAVKTVFKATLPDTAAPPGLPPAAAGPGKTSWEKGSLVSPGGLQMLLVK
  EGVQNAKTDVVVNSVPLDLVLSRGPLSKSLLEKAGPELQEELDTVGQGVAVSMGTVLKTS
  SWNLDCRYVLHVVAPEWRNGSTSSLKIMEDIIRECMEITESLSLKSIAFPAIGTGNLGFP
  KNIFAELIISEVFKFSSKNQLKTLQEVHFLLHPSDHENIQAFSDEFARRANGNLVSDKIP
  KAKDTQGFYGTVSSPDSGVYEMKIGSIIFQVASGDITKEEADVIVNSTSNSFNLKAGVSK
  AILECAGQNVERECSQQAQQRKNDYIITGGGFLRCKNIIHVIGGNDVKSSVSSVLQECEK
  KNYSSICLPAIGTGNAKQHPDKVAEAIIDAIEDFVQKGSAQSVKKVKVVIFLPQVLDVFY
  ANMKKREGTQLSSQQSVMSKLASFLGFSKQSPQKKNHLVLEKKTESATFRVCGENVTCVE
  YAISWLQDLIEKEQCPYTSEDECIKDFDEKEYQELNELQKKLNINISLDHKRPLIKVLGI
  SRDVMQARDEIEAMIKRVRLAKEQESRADCISEFIEWQYNDNNTSHCFNKMTNLKLEDAR
  REKKKTVDVKINHRHYTVNLNTYTATDTKGHSLSVQRLTKSKVDIPAHWSDMKQQNFCVV
  ELLPSDPEYNTVASKFNQTCSHFRIEKIERIQNPDLWNSYQAKKKTMDAKNGQTMNEKQL
  FHGTDAGSVPHVNRNGFNRSYAGKNAVAYGKGTYFAVNANYSANDTYSRPDANGRKHVYY
  VRVLTGIYTHGNHSLIVPPSKNPQNPTDLYDTVTDNVHHPSLFVAFYDYQAYPEYLITFR
  K
• Function: ADP-ribosyltransferase that mediates mono-ADP-ribosylation of glutamate residues on target proteins. In contrast to PARP1 and PARP2, it is not able to mediate poly-ADP-ribosylation. Has been shown to catalyze the mono-ADP-ribosylation of STAT1 at 'Glu-657' and 'Glu-705', thus decreasing STAT1 phosphorylation which negatively regulates pro-inflammatory cytokine production in macrophages in response to IFNG stimulation. However, the role of ADP-ribosylation in the prevention of STAT1 phosphorylation has been called into question and it has been suggested that the inhibition of phosphorylation may be the result of sumoylation of STAT1 'Lys-703'. Mono-ADP-ribosylates STAT6; enhancing STAT6-dependent transcription. In macrophages, positively regulates MRC1 expression in response to IL4 stimulation by promoting STAT6 phosphorylation. Mono-ADP-ribosylates PARP9.
• Tissue Specificity: Expressed in macrophages.
• Reactome Pathway:
  Maturation of nucleoprotein (R-HSA-9683610)
  Maturation of nucleoprotein (R-HSA-9694631)
  Nicotinamide salvaging (R-HSA-197264)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Glucagonoma	DISDU90K	Strong	Biomarker	[1]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[2]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Biomarker	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[4]
Skin disease	DISDW8R6	Strong	Biomarker	[5]
B-cell lymphoma	DISIH1YQ	moderate	Biomarker	[4]
Neoplasm	DISZKGEW	moderate	Biomarker	[4]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Disputed	Biomarker	[4]
Asthma	DISW9QNS	Limited	Biomarker	[7]

13 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 Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[13]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[22]

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 Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein mono-ADP-ribosyltransferase PARP14 (PARP14).	[21]

References

• [1] PARP-14 Promotes Survival of Mammalian but Not Pancreatic Cells Following Cytokine Treatment.Front Endocrinol (Lausanne). 2019 May 3;10:271. doi: 10.3389/fendo.2019.00271. eCollection 2019.
• [2] A Novel Relationship for Schizophrenia, Bipolar, and Major Depressive Disorder. Part 8: a Hint from Chromosome 8 High Density Association Screen.Mol Neurobiol. 2017 Oct;54(8):5868-5882. doi: 10.1007/s12035-016-0102-1. Epub 2016 Sep 22.
• [3] DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells.Mol Cancer. 2014 May 27;13:125. doi: 10.1186/1476-4598-13-125.
• [4] Research Progress on PARP14 as a Drug Target.Front Pharmacol. 2019 Mar 5;10:172. doi: 10.3389/fphar.2019.00172. eCollection 2019.
• [5] Poly-ADP ribose polymerase-14 limits severity of allergic skin disease.Immunology. 2017 Nov;152(3):451-461. doi: 10.1111/imm.12782. Epub 2017 Jul 27.
• [6] PARP14 promotes the proliferation and gemcitabine chemoresistance of pancreatic cancer cells through activation of NF-B pathway.Mol Carcinog. 2019 Jul;58(7):1291-1302. doi: 10.1002/mc.23011. Epub 2019 Apr 10.
• [7] Asthma and poly(ADP-ribose) polymerase inhibition: a new therapeutic approach.Drug Des Devel Ther. 2018 Feb 12;12:281-293. doi: 10.2147/DDDT.S150846. eCollection 2018.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] 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.
• [20] Identification of pim kinases as novel targets for PJ34 with confounding effects in PARP biology. ACS Chem Biol. 2012 Dec 21;7(12):1962-7. doi: 10.1021/cb300317y. Epub 2012 Oct 8.
• [21] 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.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.