Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTILI1DU)

• DOT Name: Protein mono-ADP-ribosyltransferase PARP10 (PARP10)
• Synonyms: EC 2.4.2.-; ADP-ribosyltransferase diphtheria toxin-like 10; ARTD10; Poly polymerase 10; PARP-10
• Gene Name: PARP10
• Related Disease:
  Ataxia-telangiectasia
  Pancreatic cancer
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Bipolar disorder
• UniProt ID: PAR10_HUMAN
• PDB ID: 2DHX; 3HKV; 5LX6; 6FXI
• EC Number: 2.4.2.-
• Pfam ID: PF00644
• Sequence:
  MVAMAEAEAGVAVEVRGLPPAVPDELLTLYFENRRRSGGGPVLSWQRLGCGGVLTFREPA
  DAERVLAQADHELHGAQLSLRPAPPRAPARLLLQGLPPGTTPQRLEQHVQALLRASGLPV
  QPCCALASPRPDRALVQLPKPLSEADVRVLEEQAQNLGLEGTLVSLARVPQARAVRVVGD
  GASVDLLLLELYLENERRSGGGPLEDLQRLPGPLGTVASFQQWQVAERVLQQEHRLQGSE
  LSLVPHYDILEPEELAENTSGGDHPSTQGPRATKHALLRTGGLVTALQGAGTVTMGSGEE
  PGQSGASLRTGPMVQGRGIMTTGSGQEPGQSGTSLRTGPMGSLGQAEQVSSMPMGSLEHE
  GLVSLRPVGLQEQEGPMSLGPVGSAGPVETSKGLLGQEGLVEIAMDSPEQEGLVGPMEIT
  MGSLEKAGPVSPGCVKLAGQEGLVEMVLLMEPGAMRFLQLYHEDLLAGLGDVALLPLEGP
  DMTGFRLCGAQASCQAAEEFLRSLLGSISCHVLCLEHPGSARFLLGPEGQHLLQGLEAQF
  QCVFGTERLATATLDTGLEEVDPTEALPVLPGNAHTLWTPDSTGGDQEDVSLEEVRELLA
  TLEGLDLDGEDWLPRELEEEGPQEQPEEEVTPGHEEEEPVAPSTVAPRWLEEEAALQLAL
  HRSLEPQGQVAEQEEAAALRQALTLSLLEQPPLEAEEPPDGGTDGKAQLVVHSAFEQDVE
  ELDRALRAALEVHVQEETVGPWRRTLPAELRARLERCHGVSVALRGDCTILRGFGAHPAR
  AARHLVALLAGPWDQSLAFPLAASGPTLAGQTLKGPWNNLERLAENTGEFQEVVRAFYDT
  LDAARSSIRVVRVERVSHPLLQQQYELYRERLLQRCERRPVEQVLYHGTTAPAVPDICAH
  GFNRSFCGRNATVYGKGVYFARRASLSVQDRYSPPNADGHKAVFVARVLTGDYGQGRRGL
  RAPPLRGPGHVLLRYDSAVDCICQPSIFVIFHDTQALPTHLITCEHVPRASPDDPSGLPG
  RSPDT
• Function: ADP-ribosyltransferase that mediates mono-ADP-ribosylation of glutamate and aspartate residues on target proteins. In contrast to PARP1 and PARP2, it is not able to mediate poly-ADP-ribosylation. Catalyzes mono-ADP-ribosylation of GSK3B, leading to negatively regulate GSK3B kinase activity. Involved in translesion DNA synthesis in response to DNA damage via its interaction with PCNA.
• Tissue Specificity: Highly expressed in spleen and thymus . Intermediate levels in liver, kidney, pancreas, prostate, testis, ovary, intestine, and leukocytes . Low expression in heart, brain, placenta, lung, skeletal muscle, and colon .
• 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

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[1]
Pancreatic cancer	DISJC981	moderate	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Disputed	Altered Expression	[3]
Metastatic malignant neoplasm	DIS86UK6	Disputed	Biomarker	[3]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[4]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nicotinamide-Adenine-Dinucleotide	DM9LRKB	Investigative	Protein mono-ADP-ribosyltransferase PARP10 (PARP10) decreases the abundance of Nicotinamide-Adenine-Dinucleotide.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein mono-ADP-ribosyltransferase PARP10 (PARP10).	[18]

References

• [1] PARP10 deficiency manifests by severe developmental delay and DNA repair defect.Neurogenetics. 2016 Oct;17(4):227-232. doi: 10.1007/s10048-016-0493-1. Epub 2016 Sep 13.
• [2] PARP10 (ARTD10) modulates mitochondrial function.PLoS One. 2018 Jan 2;13(1):e0187789. doi: 10.1371/journal.pone.0187789. eCollection 2018.
• [3] PARP10 suppresses tumor metastasis through regulation of Aurora A activity.Oncogene. 2018 May;37(22):2921-2935. doi: 10.1038/s41388-018-0168-5. Epub 2018 Mar 8.
• [4] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [5] 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.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [12] 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.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [16] 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.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity. J Biol Chem. 2020 Dec 25;295(52):17986-17996. doi: 10.1074/jbc.RA120.015138. Epub 2020 Oct 13.