Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPZDGW7)

• DOT Name: PCNA-interacting partner (PARPBP)
• Synonyms: PARI; PARP-1 binding protein; PARP1-binding protein; PARPBP
• Gene Name: PARPBP
• Related Disease:
  Advanced cancer
  Congenital alveolar dysplasia
  Fanconi anemia complementation group A
  Fanconi's anemia
  Hepatocellular carcinoma
  Male infertility
  Matthew-Wood syndrome
  Pancreatic cancer
  Pancreatic tumour
  Cryptorchidism
  Gastric cancer
  Stomach cancer
• UniProt ID: PARI_HUMAN
• Sequence:
  MAVFNQKSVSDMIKEFRKNWRALCNSERTTLCGADSMLLALQLSMAENNKQHSGEFTVSL
  SDVLLTWKYLLHEKLNLPVENMDVTDHYEDVRKIYDDFLKNSNMLDLIDVYQKCRALTSN
  CENYNTVSPSQLLDFLSGKQYAVGDETDLSIPTSPTSKYNRDNEKVQLLARKIIFSYLNL
  LVNSKNDLAVAYILNIPDRGLGREAFTDLKHAAREKQMSIFLVATSFIRTIELGGKGYAP
  PPSDPLRTHVKGLSNFINFIDKLDEILGEIPNPSIAGGQILSVIKMQLIKGQNSRDPFCK
  AIEEVAQDLDLRIKNIINSQEGVVALSTTDISPARPKSHAINHGTAYCGRDTVKALLVLL
  DEEAANAPTKNKAELLYDEENTIHHHGTSILTLFRSPTQVNNSIKPLRERICVSMQEKKI
  KMKQTLIRSQFACTYKDDYMISKDNWNNVNLASKPLCVLYMENDLSEGVNPSVGRSTIGT
  SFGNVHLDRSKNEKVSRKSTSQTGNKSSKRKQVDLDGENILCDNRNEPPQHKNAKIPKKS
  NDSQNRLYGKLAKVAKSNKCTAKDKLISGQAKLTQFFRL
• Function: Required to suppress inappropriate homologous recombination, thereby playing a central role DNA repair and in the maintenance of genomic stability. Antagonizes homologous recombination by interfering with the formation of the RAD51-DNA homologous recombination structure. Binds single-strand DNA and poly(A) homopolymers. Positively regulate the poly(ADP-ribosyl)ation activity of PARP1; however such function may be indirect.
• Tissue Specificity: Restricted to testis. Overexpressed in multiple cancer cells.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Congenital alveolar dysplasia	DIS1IYUN	Strong	Biomarker	[2]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[3]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Male infertility	DISY3YZZ	Strong	Biomarker	[4]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[5]
Pancreatic cancer	DISJC981	Strong	Biomarker	[1]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[5]
Cryptorchidism	DISYUD2P	Limited	Genetic Variation	[6]
Gastric cancer	DISXGOUK	Limited	Biomarker	[7]
Stomach cancer	DISKIJSX	Limited	Biomarker	[7]

18 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 PCNA-interacting partner (PARPBP).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of PCNA-interacting partner (PARPBP).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of PCNA-interacting partner (PARPBP).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of PCNA-interacting partner (PARPBP).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of PCNA-interacting partner (PARPBP).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of PCNA-interacting partner (PARPBP).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of PCNA-interacting partner (PARPBP).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of PCNA-interacting partner (PARPBP).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of PCNA-interacting partner (PARPBP).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of PCNA-interacting partner (PARPBP).	[15]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of PCNA-interacting partner (PARPBP).	[17]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of PCNA-interacting partner (PARPBP).	[18]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of PCNA-interacting partner (PARPBP).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of PCNA-interacting partner (PARPBP).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of PCNA-interacting partner (PARPBP).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of PCNA-interacting partner (PARPBP).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of PCNA-interacting partner (PARPBP).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of PCNA-interacting partner (PARPBP).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of PCNA-interacting partner (PARPBP).	[21]

References

• [1] Overexpression of PARPBP Correlates with Tumor Progression and Poor Prognosis in Hepatocellular Carcinoma.Dig Dis Sci. 2019 Oct;64(10):2878-2892. doi: 10.1007/s10620-019-05608-4. Epub 2019 Apr 4.
• [2] Combined measurement of fetal lung volume and pulmonary artery resistance index is more accurate for prediction of neonatal respiratory distress syndrome in preterm fetuses: a pilot study.J Matern Fetal Neonatal Med. 2019 Feb;32(4):626-632. doi: 10.1080/14767058.2017.1387891. Epub 2017 Oct 12.
• [3] Inhibition of homologous recombination by the PCNA-interacting protein PARI.Mol Cell. 2012 Jan 13;45(1):75-86. doi: 10.1016/j.molcel.2011.11.010. Epub 2011 Dec 6.
• [4] Estrogen promotes Leydig cell engulfment by macrophages in male infertility.J Clin Invest. 2014 Jun;124(6):2709-21. doi: 10.1172/JCI59901. Epub 2014 Apr 24.
• [5] PARI overexpression promotes genomic instability and pancreatic tumorigenesis.Cancer Res. 2013 Apr 15;73(8):2529-39. doi: 10.1158/0008-5472.CAN-12-3313. Epub 2013 Feb 22.
• [6] Altered structure and function of reproductive organs in transgenic male mice overexpressing human aromatase.Endocrinology. 2001 Jun;142(6):2435-42. doi: 10.1210/endo.142.6.8211.
• [7] PARI functions as a new transcriptional target of FOXM1 involved in gastric cancer development.Int J Biol Sci. 2018 Apr 5;14(5):531-541. doi: 10.7150/ijbs.23945. 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] 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.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] 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.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [18] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [19] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [20] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [21] 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.
• [22] 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.
• [23] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.