Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT54LG0P)

• DOT Name: Polyadenylate-binding protein 1 (PABPC1)
• Synonyms: PABP-1; Poly(A)-binding protein 1
• Gene Name: PABPC1
• UniProt ID: PABP1_HUMAN
• PDB ID: 1CVJ; 1G9L; 1JGN; 1JH4; 2K8G; 2RQG; 2RQH; 2X04; 3KTP; 3KTR; 3KUI; 3KUJ; 3KUR; 3KUS; 3KUT; 3PKN; 3PTH; 4F02; 4F25; 4F26; 5DX1; 5DX8; 5DXA; 5LGP; 5LGQ; 5LGR; 5LGS; 7BN3
• Pfam ID: PF00658 ; PF00076
• Sequence:
  MNPSAPSYPMASLYVGDLHPDVTEAMLYEKFSPAGPILSIRVCRDMITRRSLGYAYVNFQ
  QPADAERALDTMNFDVIKGKPVRIMWSQRDPSLRKSGVGNIFIKNLDKSIDNKALYDTFS
  AFGNILSCKVVCDENGSKGYGFVHFETQEAAERAIEKMNGMLLNDRKVFVGRFKSRKERE
  AELGARAKEFTNVYIKNFGEDMDDERLKDLFGKFGPALSVKVMTDESGKSKGFGFVSFER
  HEDAQKAVDEMNGKELNGKQIYVGRAQKKVERQTELKRKFEQMKQDRITRYQGVNLYVKN
  LDDGIDDERLRKEFSPFGTITSAKVMMEGGRSKGFGFVCFSSPEEATKAVTEMNGRIVAT
  KPLYVALAQRKEERQAHLTNQYMQRMASVRAVPNPVINPYQPAPPSGYFMAAIPQTQNRA
  AYYPPSQIAQLRPSPRWTAQGARPHPFQNMPGAIRPAAPRPPFSTMRPASSQVPRVMSTQ
  RVANTSTQTMGPRPAAAAAAATPAVRTVPQYKYAAGVRNPQQHLNAQPQVTMQQPAVHVQ
  GQEPLTASMLASAPPQEQKQMLGERLFPLIQAMHPTLAGKITGMLLEIDNSELLHMLESP
  ESLRSKVDEAVAVLQAHQAKEAAQKAVNSATGVPTV
• Function: Binds the poly(A) tail of mRNA, including that of its own transcript, and regulates processes of mRNA metabolism such as pre-mRNA splicing and mRNA stability. Its function in translational initiation regulation can either be enhanced by PAIP1 or repressed by PAIP2. Can probably bind to cytoplasmic RNA sequences other than poly(A) in vivo. Binds to N6-methyladenosine (m6A)-containing mRNAs and contributes to MYC stability by binding to m6A-containing MYC mRNAs. Involved in translationally coupled mRNA turnover. Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain. Involved in regulation of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons; for the recognition of premature termination codons (PTC) and initiation of NMD a competitive interaction between UPF1 and PABPC1 with the ribosome-bound release factors is proposed. By binding to long poly(A) tails, may protect them from uridylation by ZCCHC6/ZCCHC11 and hence contribute to mRNA stability ; (Microbial infection) Positively regulates the replication of dengue virus (DENV).
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  R. degradation (hsa03018)
• Reactome Pathway:
  Deadenylation of mRNA (R-HSA-429947)
  AUF1 (hnRNP D0) binds and destabilizes mRNA (R-HSA-450408)
  Translation initiation complex formation (R-HSA-72649)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) (R-HSA-975956)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  M-decay (R-HSA-9820841)
  Z-decay (R-HSA-9820865)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

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 Polyadenylate-binding protein 1 (PABPC1).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Polyadenylate-binding protein 1 (PABPC1).	[5]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Polyadenylate-binding protein 1 (PABPC1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Polyadenylate-binding protein 1 (PABPC1).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Polyadenylate-binding protein 1 (PABPC1).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Polyadenylate-binding protein 1 (PABPC1).	[4]
Marinol	DM70IK5	Approved	Marinol increases the expression of Polyadenylate-binding protein 1 (PABPC1).	[6]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Polyadenylate-binding protein 1 (PABPC1).	[7]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Polyadenylate-binding protein 1 (PABPC1).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Polyadenylate-binding protein 1 (PABPC1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Polyadenylate-binding protein 1 (PABPC1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Polyadenylate-binding protein 1 (PABPC1).	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Polyadenylate-binding protein 1 (PABPC1).	[13]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Polyadenylate-binding protein 1 (PABPC1).	[14]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of Polyadenylate-binding protein 1 (PABPC1).	[15]
torin 1	DMZD0NA	Investigative	torin 1 decreases the expression of Polyadenylate-binding protein 1 (PABPC1).	[15]

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] 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.
• [3] 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.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [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] 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.
• [8] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] 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.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [13] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [14] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [15] La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1). J Biol Chem. 2015 Jun 26;290(26):15996-6020. doi: 10.1074/jbc.M114.621730. Epub 2015 May 4.