Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYL81ZI)

• DOT Name: Poly polymerase 2 (PARP2)
• Synonyms: PARP-2; hPARP-2; EC 2.4.2.30; ADP-ribosyltransferase diphtheria toxin-like 2; ARTD2; DNA ADP-ribosyltransferase PARP2; EC 2.4.2.-; NAD(+) ADP-ribosyltransferase 2; ADPRT-2; Poly synthase 2; pADPRT-2; Protein poly-ADP-ribosyltransferase PARP2; EC 2.4.2.-
• Gene Name: PARP2
• UniProt ID: PARP2_HUMAN
• PDB ID: 3KCZ; 3KJD; 4PJV; 4TVJ; 4ZZX; 4ZZY; 5D5K; 5DSY; 6F1K; 6F5B; 6F5F; 6TX3; 6USJ; 6X0L; 6X0M; 6X0N; 7AEO; 7R59; 8HE8
• EC Number: 2.4.2.-; 2.4.2.30
• Pfam ID: PF00644 ; PF02877 ; PF05406
• Sequence:
  MAARRRRSTGGGRARALNESKRVNNGNTAPEDSSPAKKTRRCQRQESKKMPVAGGKANKD
  RTEDKQDGMPGRSWASKRVSESVKALLLKGKAPVDPECTAKVGKAHVYCEGNDVYDVMLN
  QTNLQFNNNKYYLIQLLEDDAQRNFSVWMRWGRVGKMGQHSLVACSGNLNKAKEIFQKKF
  LDKTKNNWEDREKFEKVPGKYDMLQMDYATNTQDEEETKKEESLKSPLKPESQLDLRVQE
  LIKLICNVQAMEEMMMEMKYNTKKAPLGKLTVAQIKAGYQSLKKIEDCIRAGQHGRALME
  ACNEFYTRIPHDFGLRTPPLIRTQKELSEKIQLLEALGDIEIAIKLVKTELQSPEHPLDQ
  HYRNLHCALRPLDHESYEFKVISQYLQSTHAPTHSDYTMTLLDLFEVEKDGEKEAFREDL
  HNRMLLWHGSRMSNWVGILSHGLRIAPPEAPITGYMFGKGIYFADMSSKSANYCFASRLK
  NTGLLLLSEVALGQCNELLEANPKAEGLLQGKHSTKGLGKMAPSSAHFVTLNGSTVPLGP
  ASDTGILNPDGYTLNYNEYIVYNPNQVRMRYLLKVQFNFLQLW
• Function: Poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair. Mediates glutamate, aspartate or serine ADP-ribosylation of proteins: the ADP-D-ribosyl group of NAD(+) is transferred to the acceptor carboxyl group of target residues and further ADP-ribosyl groups are transferred to the 2'-position of the terminal adenosine moiety, building up a polymer with an average chain length of 20-30 units. Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage. Mediates glutamate and aspartate ADP-ribosylation of target proteins in absence of HPF1. Following interaction with HPF1, catalyzes serine ADP-ribosylation of target proteins; HPF1 conferring serine specificity by completing the PARP2 active site. PARP2 initiates the repair of double-strand DNA breaks: recognizes and binds DNA breaks within chromatin and recruits HPF1, licensing serine ADP-ribosylation of target proteins, such as histones, thereby promoting decompaction of chromatin and the recruitment of repair factors leading to the reparation of DNA strand breaks. HPF1 initiates serine ADP-ribosylation but restricts the polymerase activity of PARP2 in order to limit the length of poly-ADP-ribose chains. Specifically mediates formation of branched poly-ADP-ribosylation. Branched poly-ADP-ribose chains are specifically recognized by some factors, such as APLF. In addition to proteins, also able to ADP-ribosylate DNA: preferentially acts on 5'-terminal phosphates at DNA strand breaks termini in nicked duplex.
• Tissue Specificity: Widely expressed, mainly in actively dividing tissues . The highest levels are in the brain, heart, pancreas, skeletal muscle and testis; also detected in kidney, liver, lung, placenta, ovary and spleen; levels are low in leukocytes, colon, small intestine, prostate and thymus .
• KEGG Pathway:
  Base excision repair (hsa03410)
  Apoptosis (hsa04210)
• Reactome Pathway:
  HDR through MMEJ (alt-NHEJ) (R-HSA-5685939)
  DNA Damage Recognition in GG-NER (R-HSA-5696394)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  Dual Incision in GG-NER (R-HSA-5696400)
  POLB-Dependent Long Patch Base Excision Repair (R-HSA-110362)

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
Gemcitabine	DMSE3I7	Approved	Poly polymerase 2 (PARP2) decreases the response to substance of Gemcitabine.	[18]
3-aminobenzamide	DM7P3IZ	Investigative	Poly polymerase 2 (PARP2) affects the binding of 3-aminobenzamide.	[19]

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 Poly polymerase 2 (PARP2).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Poly polymerase 2 (PARP2).	[14]

18 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 Poly polymerase 2 (PARP2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Poly polymerase 2 (PARP2).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Poly polymerase 2 (PARP2).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Poly polymerase 2 (PARP2).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Poly polymerase 2 (PARP2).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Poly polymerase 2 (PARP2).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Poly polymerase 2 (PARP2).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Poly polymerase 2 (PARP2).	[8]
Talazoparib	DM1KS78	Approved	Talazoparib decreases the activity of Poly polymerase 2 (PARP2).	[9]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Poly polymerase 2 (PARP2).	[10]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin increases the expression of Poly polymerase 2 (PARP2).	[11]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 increases the expression of Poly polymerase 2 (PARP2).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Poly polymerase 2 (PARP2).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Poly polymerase 2 (PARP2).	[13]
PJ34	DMXO6YH	Preclinical	PJ34 decreases the activity of Poly polymerase 2 (PARP2).	[9]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Poly polymerase 2 (PARP2).	[15]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Poly polymerase 2 (PARP2).	[16]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Poly polymerase 2 (PARP2).	[17]

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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] 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.
• [5] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors. J Med Chem. 2017 Feb 23;60(4):1262-1271. doi: 10.1021/acs.jmedchem.6b00990. Epub 2016 Dec 21.
• [10] Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis. Environ Mol Mutagen. 2009 Jan;50(1):46-59.
• [11] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [17] Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways. Environ Int. 2020 Feb;135:105414. doi: 10.1016/j.envint.2019.105414. Epub 2019 Dec 23.
• [18] Synergistic chemosensitivity of triple-negative breast cancer cell lines to poly(ADP-Ribose) polymerase inhibition, gemcitabine, and cisplatin. Cancer Res. 2010 Oct 15;70(20):7970-80. doi: 10.1158/0008-5472.CAN-09-4521. Epub 2010 Aug 26.
• [19] Crystal structure of the catalytic domain of human PARP2 in complex with PARP inhibitor ABT-888. Biochemistry. 2010 Feb 16;49(6):1056-8. doi: 10.1021/bi902079y.