Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBR2Q0F)

• DOT Name: Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1)
• Synonyms: EC 2.7.7.8; 3'-5' RNA exonuclease OLD35; PNPase old-35; Polynucleotide phosphorylase 1; PNPase 1; Polynucleotide phosphorylase-like protein
• Gene Name: PNPT1
• Related Disease:
  Combined oxidative phosphorylation defect type 13
  Advanced cancer
  Chronic obstructive pulmonary disease
  Colon adenocarcinoma
  Deafness
  Hypothyroidism
  Pancreatic cancer
  Prostate adenocarcinoma
  Sensorineural hearing loss disorder
  Intellectual disability
  Leigh syndrome
  Neuroblastoma
  Hearing loss, autosomal recessive
  Autosomal recessive nonsyndromic hearing loss 70
  Dystonia
  Hepatocellular carcinoma
  Melanoma
  Neoplasm
  Spinocerebellar ataxia type 25
• UniProt ID: PNPT1_HUMAN
• PDB ID: 3U1K; 5ZF6
• EC Number: 2.7.7.8
• Pfam ID: PF00013 ; PF03726 ; PF01138 ; PF03725 ; PF00575
• Sequence:
  MAACRYCCSCLRLRPLSDGPFLLPRRDRALTQLQVRALWSSAGSRAVAVDLGNRKLEISS
  GKLARFADGSAVVQSGDTAVMVTAVSKTKPSPSQFMPLVVDYRQKAAAAGRIPTNYLRRE
  IGTSDKEILTSRIIDRSIRPLFPAGYFYDTQVLCNLLAVDGVNEPDVLAINGASVALSLS
  DIPWNGPVGAVRIGIIDGEYVVNPTRKEMSSSTLNLVVAGAPKSQIVMLEASAENILQQD
  FCHAIKVGVKYTQQIIQGIQQLVKETGVTKRTPQKLFTPSPEIVKYTHKLAMERLYAVFT
  DYEHDKVSRDEAVNKIRLDTEEQLKEKFPEADPYEIIESFNVVAKEVFRSIVLNEYKRCD
  GRDLTSLRNVSCEVDMFKTLHGSALFQRGQTQVLCTVTFDSLESGIKSDQVITAINGIKD
  KNFMLHYEFPPYATNEIGKVTGLNRRELGHGALAEKALYPVIPRDFPFTIRVTSEVLESN
  GSSSMASACGGSLALMDSGVPISSAVAGVAIGLVTKTDPEKGEIEDYRLLTDILGIEDYN
  GDMDFKIAGTNKGITALQADIKLPGIPIKIVMEAIQQASVAKKEILQIMNKTISKPRASR
  KENGPVVETVQVPLSKRAKFVGPGGYNLKKLQAETGVTISQVDEETFSVFAPTPSAMHEA
  RDFITEICKDDQEQQLEFGAVYTATITEIRDTGVMVKLYPNMTAVLLHNTQLDQRKIKHP
  TALGLEVGQEIQVKYFGRDPADGRMRLSRKVLQSPATTVVRTLNDRSSIVMGEPISQSSS
  NSQ
• Function: RNA-binding protein implicated in numerous RNA metabolic processes. Catalyzes the phosphorolysis of single-stranded polyribonucleotides processively in the 3'-to-5' direction. Mitochondrial intermembrane factor with RNA-processing exoribonulease activity. Component of the mitochondrial degradosome (mtEXO) complex, that degrades 3' overhang double-stranded RNA with a 3'-to-5' directionality in an ATP-dependent manner. Involved in the degradation of non-coding mitochondrial transcripts (MT-ncRNA) and tRNA-like molecules. Required for correct processing and polyadenylation of mitochondrial mRNAs. Plays a role as a cytoplasmic RNA import factor that mediates the translocation of small RNA components, like the 5S RNA, the RNA subunit of ribonuclease P and the mitochondrial RNA-processing (MRP) RNA, into the mitochondrial matrix. Plays a role in mitochondrial morphogenesis and respiration; regulates the expression of the electron transport chain (ETC) components at the mRNA and protein levels. In the cytoplasm, shows a 3'-to-5' exoribonuclease mediating mRNA degradation activity; degrades c-myc mRNA upon treatment with IFNB1/IFN-beta, resulting in a growth arrest in melanoma cells. Regulates the stability of specific mature miRNAs in melanoma cells; specifically and selectively degrades miR-221, preferentially. Also plays a role in RNA cell surveillance by cleaning up oxidized RNAs. Binds to the RNA subunit of ribonuclease P, MRP RNA and miR-221 microRNA.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway: Mitochondrial RNA degradation (R-HSA-9836573)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Combined oxidative phosphorylation defect type 13	DIS4Q3XX	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Altered Expression	[3]
Colon adenocarcinoma	DISDRE0J	Strong	Altered Expression	[3]
Deafness	DISKCLH4	Strong	Biomarker	[4]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[5]
Pancreatic cancer	DISJC981	Strong	Biomarker	[2]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[3]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[6]
Intellectual disability	DISMBNXP	moderate	Biomarker	[7]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[8]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[9]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[10]
Autosomal recessive nonsyndromic hearing loss 70	DISEPSRN	Limited	Unknown	[10]
Dystonia	DISJLFGW	Limited	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[11]
Melanoma	DIS1RRCY	Limited	Biomarker	[12]
Neoplasm	DISZKGEW	Limited	Altered Expression	[13]
Spinocerebellar ataxia type 25	DIS6NFPX	Limited	Autosomal dominant	[14]

1 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 Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[15]

14 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 Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[22]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[23]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[27]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Polyribonucleotide nucleotidyltransferase 1, mitochondrial (PNPT1).	[28]

References

• [1] Mutation in PNPT1, which encodes a polyribonucleotide nucleotidyltransferase, impairs RNA import into mitochondria and causes respiratory-chain deficiency. Am J Hum Genet. 2012 Nov 2;91(5):912-8. doi: 10.1016/j.ajhg.2012.09.001. Epub 2012 Oct 18.
• [2] Progression elevated gene-3 promoter (PEG-Prom) confers cancer cell selectivity to human polynucleotide phosphorylase (hPNPase(old-35))-mediated growth suppression.J Cell Physiol. 2008 May;215(2):401-9. doi: 10.1002/jcp.21320.
• [3] Analysis of global changes in gene expression induced by human polynucleotide phosphorylase (hPNPase(old-35)).J Cell Physiol. 2014 Dec;229(12):1952-62. doi: 10.1002/jcp.24645.
• [4] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [5] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [6] Is PNPT1-related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1-related disorders.Am J Med Genet A. 2018 Nov;176(11):2487-2493. doi: 10.1002/ajmg.a.40516. Epub 2018 Sep 23.
• [7] Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants.J Clin Med. 2019 Nov 19;8(11):2020. doi: 10.3390/jcm8112020.
• [8] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [9] Adenovirus-mediated hPNPase(old-35) gene transfer as a therapeutic strategy for neuroblastoma.J Cell Physiol. 2009 Jun;219(3):707-15. doi: 10.1002/jcp.21719.
• [10] A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss. Am J Hum Genet. 2012 Nov 2;91(5):919-27. doi: 10.1016/j.ajhg.2012.09.002. Epub 2012 Oct 18.
• [11] Hepatocellular carcinoma-associated protein markers investigated by MALDI-TOF MS.Mol Med Rep. 2010 Jul-Aug;3(4):589-96. doi: 10.3892/mmr_00000302.
• [12] Identification of genes potentially regulated by human polynucleotide phosphorylase (hPNPase old-35) using melanoma as a model.PLoS One. 2013 Oct 15;8(10):e76284. doi: 10.1371/journal.pone.0076284. eCollection 2013.
• [13] Human polynucleotide phosphorylase selectively and preferentially degrades microRNA-221 in human melanoma cells.Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11948-53. doi: 10.1073/pnas.0914143107. Epub 2010 Jun 14.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [19] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [20] 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.
• [21] 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.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [24] 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.
• [25] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [26] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [27] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [28] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.