Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3MC5SE)

• DOT Name: Polyadenylate-binding protein 2 (PABPN1)
• Synonyms: PABP-2; Poly(A)-binding protein 2; Nuclear poly(A)-binding protein 1; Poly(A)-binding protein II; PABII; Polyadenylate-binding nuclear protein 1
• Gene Name: PABPN1
• Related Disease:
  Oculopharyngeal muscular dystrophy
  Oculopharyngodistal myopathy
  Alzheimer disease
  Bone Paget disease
  Frontotemporal dementia
  Influenza
  Leukoplakia
  Muscular dystrophy
  Myopathy
  Neoplasm
  Neuromuscular disease
  Night blindness
  Non-small-cell lung cancer
  Oral cancer
  Pick disease
  Ptosis
  Amyotrophic lateral sclerosis
• UniProt ID: PABP2_HUMAN
• PDB ID: 3B4D; 3B4M; 3UCG
• Pfam ID: PF00076
• Sequence:
  MAAAAAAAAAAGAAGGRGSGPGRRRHLVPGAGGEAGEGAPGGAGDYGNGLESEELEPEEL
  LLEPEPEPEPEEEPPRPRAPPGAPGPGPGSGAPGSQEEEEEPGLVEGDPGDGAIEDPELE
  AIKARVREMEEEAEKLKELQNEVEKQMNMSPPPGNAGPVIMSIEEKMEADARSIYVGNVD
  YGATAEELEAHFHGCGSVNRVTILCDKFSGHPKGFAYIEFSDKESVRTSLALDESLFRGR
  QIKVIPKRTNRPGISTTDRGFPRARYRARTTNYNSSRSRFYSGFNSRPRGRVYRGRARAT
  SWYSPY
• Function: Involved in the 3'-end formation of mRNA precursors (pre-mRNA) by the addition of a poly(A) tail of 200-250 nt to the upstream cleavage product. Stimulates poly(A) polymerase (PAPOLA) conferring processivity on the poly(A) tail elongation reaction and controls also the poly(A) tail length. Increases the affinity of poly(A) polymerase for RNA. Is also present at various stages of mRNA metabolism including nucleocytoplasmic trafficking and nonsense-mediated decay (NMD) of mRNA. Cooperates with SKIP to synergistically activate E-box-mediated transcription through MYOD1 and may regulate the expression of muscle-specific genes. Binds to poly(A) and to poly(G) with high affinity. May protect the poly(A) tail from degradation. Subunit of the trimeric poly(A) tail exosome targeting (PAXT) complex, a complex that directs a subset of long and polyadenylated poly(A) RNAs for exosomal degradation. The RNA exosome is fundamental for the degradation of RNA in eukaryotic nuclei. Substrate targeting is facilitated by its cofactor MTREX, which links to RNA-binding protein adapters.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Influenza A (hsa05164)
• Reactome Pathway:
  mRNA 3'-end processing (R-HSA-72187)
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Processing of Intronless Pre-mRNAs (R-HSA-77595)
  Z-decay (R-HSA-9820865)
  Inhibition of Host mRNA Processing and RNA Silencing (R-HSA-168315)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Oculopharyngeal muscular dystrophy	DISF4G07	Definitive	Autosomal dominant	[1]
Oculopharyngodistal myopathy	DISGCD9O	Definitive	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Bone Paget disease	DISIPS4V	Strong	Biomarker	[4]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[4]
Influenza	DIS3PNU3	Strong	Biomarker	[5]
Leukoplakia	DIST3QD3	Strong	Biomarker	[6]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[7]
Myopathy	DISOWG27	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[9]
Night blindness	DIS335K9	Strong	Genetic Variation	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[8]
Oral cancer	DISLD42D	Strong	Biomarker	[11]
Pick disease	DISP6X50	Strong	Genetic Variation	[4]
Ptosis	DISJZNIY	Strong	Genetic Variation	[12]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Altered Expression	[13]

9 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 Polyadenylate-binding protein 2 (PABPN1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Polyadenylate-binding protein 2 (PABPN1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Polyadenylate-binding protein 2 (PABPN1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Polyadenylate-binding protein 2 (PABPN1).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Polyadenylate-binding protein 2 (PABPN1).	[18]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Polyadenylate-binding protein 2 (PABPN1).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Polyadenylate-binding protein 2 (PABPN1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Polyadenylate-binding protein 2 (PABPN1).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Polyadenylate-binding protein 2 (PABPN1).	[22]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Autosomal recessive oculopharyngodistal myopathy: a distinct phenotypical, histological, and genetic entity.J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1499-501. doi: 10.1136/jnnp.2003.025072.
• [3] Prevention of oculopharyngeal muscular dystrophy by muscular expression of Llama single-chain intrabodies in vivo.Hum Mol Genet. 2009 May 15;18(10):1849-59. doi: 10.1093/hmg/ddp101. Epub 2009 Mar 3.
• [4] Nuclear inclusions mimicking poly(A)-binding protein nuclear 1 inclusions in a case of inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia with a novel mutation in the valosin-containing protein gene.Neuromuscul Disord. 2016 Jul;26(7):436-40. doi: 10.1016/j.nmd.2016.05.001. Epub 2016 May 5.
• [5] Effects of the C-terminal truncation in NS1 protein of the 2009 pandemic H1N1 influenza virus on host gene expression.PLoS One. 2011;6(10):e26175. doi: 10.1371/journal.pone.0026175. Epub 2011 Oct 12.
• [6] Variants in FAT1 and COL9A1 genes in male population with or without substance use to assess the risk factors for oral malignancy.PLoS One. 2019 Jan 18;14(1):e0210901. doi: 10.1371/journal.pone.0210901. eCollection 2019.
• [7] Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing.Nucleic Acids Res. 2017 Oct 13;45(18):10706-10725. doi: 10.1093/nar/gkx786.
• [8] Alternative polyadenylation is associated with lower expression of PABPN1 and poor prognosis in non-small cell lung cancer.Cancer Sci. 2014 Sep;105(9):1135-41. doi: 10.1111/cas.12472. Epub 2014 Sep 3.
• [9] Mutation and haplotype analysis of oculopharyngeal muscular dystrophy in Thai patients.J Clin Neurosci. 2011 May;18(5):674-7. doi: 10.1016/j.jocn.2010.08.020.
• [10] Homozygosity for a Recessive Loss-of-Function Mutation of the NRL Gene Is Associated With a Variant of Enhanced S-Cone Syndrome.Invest Ophthalmol Vis Sci. 2016 Oct 1;57(13):5361-5371. doi: 10.1167/iovs.16-19505.
• [11] Fluorescence visualization improves the detection of oral, potentially malignant, disorders in population screening.Photodiagnosis Photodyn Ther. 2019 Sep;27:74-78. doi: 10.1016/j.pdpdt.2019.05.017. Epub 2019 May 19.
• [12] Oculopharyngeal muscular dystrophy with PABPN1 mutation in a Chinese Malaysian woman.Neuromuscul Disord. 2005 Mar;15(3):262-4. doi: 10.1016/j.nmd.2004.10.016. Epub 2005 Jan 28.
• [13] PABPN1 suppresses TDP-43 toxicity in ALS disease models.Hum Mol Genet. 2015 Sep 15;24(18):5154-73. doi: 10.1093/hmg/ddv238. Epub 2015 Jun 30.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [17] 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.
• [18] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] 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.
• [22] 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.