Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTG4PE3)

• DOT Name: Poly(A)-specific ribonuclease PARN (PARN)
• Synonyms: EC 3.1.13.4; Deadenylating nuclease; Deadenylation nuclease; Polyadenylate-specific ribonuclease
• Gene Name: PARN
• Related Disease:
  Dyskeratosis congenita, autosomal recessive 6
  Dyskeratosis congenita, X-linked
  Acute leukaemia
  Acute lymphocytic leukaemia
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Childhood acute lymphoblastic leukemia
  Connective tissue disorder
  Dorfman-Chanarin disease
  Hypersensitivity pneumonitis
  Idiopathic interstitial pneumonia
  Lafora disease
  Lung squamous cell carcinoma
  Mental disorder
  Nervous system disease
  Non-small-cell lung cancer
  Pancytopenia
  Pulmonary fibrosis
  Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4
  Renal fibrosis
  Telomere syndrome
  Neoplasm
  Dyskeratosis congenita
  Hoyeraal-Hreidarsson syndrome
  Hereditary hemochromatosis
  Pancreatic cancer
• UniProt ID: PARN_HUMAN
• PDB ID: 2A1R; 2A1S; 3CTR
• EC Number: 3.1.13.4
• Pfam ID: PF04857 ; PF08675
• Sequence:
  MEIIRSNFKSNLHKVYQAIEEADFFAIDGEFSGISDGPSVSALTNGFDTPEERYQKLKKH
  SMDFLLFQFGLCTFKYDYTDSKYITKSFNFYVFPKPFNRSSPDVKFVCQSSSIDFLASQG
  FDFNKVFRNGIPYLNQEEERQLREQYDEKRSQANGAGALSYVSPNTSKCPVTIPEDQKKF
  IDQVVEKIEDLLQSEENKNLDLEPCTGFQRKLIYQTLSWKYPKGIHVETLETEKKERYIV
  ISKVDEEERKRREQQKHAKEQEELNDAVGFSRVIHAIANSGKLVIGHNMLLDVMHTVHQF
  YCPLPADLSEFKEMTTCVFPRLLDTKLMASTQPFKDIINNTSLAELEKRLKETPFNPPKV
  ESAEGFPSYDTASEQLHEAGYDAYITGLCFISMANYLGSFLSPPKIHVSARSKLIEPFFN
  KLFLMRVMDIPYLNLEGPDLQPKRDHVLHVTFPKEWKTSDLYQLFSAFGNIQISWIDDTS
  AFVSLSQPEQVKIAVNTSKYAESYRIQTYAEYMGRKQEEKQIKRKWTEDSWKEADSKRLN
  PQCIPYTLQNHYYRNNSFTAPSTVGKRNLSPSQEEAGLEDGVSGEISDTELEQTDSCAEP
  LSEGRKKAKKLKRMKKELSPAGSISKNSPATLFEVPDTW
• Function: 3'-exoribonuclease that has a preference for poly(A) tails of mRNAs, thereby efficiently degrading poly(A) tails. Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs and is also used to silence certain maternal mRNAs translationally during oocyte maturation and early embryonic development. Interacts with both the 3'-end poly(A) tail and the 5'-end cap structure during degradation, the interaction with the cap structure being required for an efficient degradation of poly(A) tails. Involved in nonsense-mediated mRNA decay, a critical process of selective degradation of mRNAs that contain premature stop codons. Also involved in degradation of inherently unstable mRNAs that contain AU-rich elements (AREs) in their 3'-UTR, possibly via its interaction with KHSRP. Probably mediates the removal of poly(A) tails of AREs mRNAs, which constitutes the first step of destabilization. Also able to recognize and trim poly(A) tails of microRNAs such as MIR21 and H/ACA box snoRNAs (small nucleolar RNAs) leading to microRNAs degradation or snoRNA increased stability.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway:
  Deadenylation of mRNA (R-HSA-429947)
  KSRP (KHSRP) binds and destabilizes mRNA (R-HSA-450604)
  ATF4 activates genes in response to endoplasmic reticulum stress (R-HSA-380994)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dyskeratosis congenita, autosomal recessive 6	DISS84LS	Definitive	Autosomal recessive	[1]
Dyskeratosis congenita, X-linked	DISJ3Y69	Definitive	Genetic Variation	[2]
Acute leukaemia	DISDQFDI	Strong	Biomarker	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Posttranslational Modification	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Posttranslational Modification	[3]
Connective tissue disorder	DISKXBS3	Strong	Biomarker	[6]
Dorfman-Chanarin disease	DISKKT3R	Strong	Genetic Variation	[7]
Hypersensitivity pneumonitis	DIS5IW5K	Strong	Biomarker	[6]
Idiopathic interstitial pneumonia	DISH7LPY	Strong	Biomarker	[6]
Lafora disease	DIS83JHH	Strong	Biomarker	[8]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[9]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[10]
Nervous system disease	DISJ7GGT	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[11]
Pancytopenia	DISVKEHV	Strong	Genetic Variation	[10]
Pulmonary fibrosis	DISQKVLA	Strong	Genetic Variation	[12]
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4	DISKACXA	Strong	Autosomal dominant	[13]
Renal fibrosis	DISMHI3I	Strong	Genetic Variation	[14]
Telomere syndrome	DISLXQHV	Strong	Genetic Variation	[14]
Neoplasm	DISZKGEW	moderate	Biomarker	[11]
Dyskeratosis congenita	DISSXV0K	Supportive	Autosomal dominant	[1]
Hoyeraal-Hreidarsson syndrome	DISAUR8F	Supportive	Autosomal dominant	[1]
Hereditary hemochromatosis	DISVG5MT	Limited	Genetic Variation	[15]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Poly(A)-specific ribonuclease PARN (PARN).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Poly(A)-specific ribonuclease PARN (PARN).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Poly(A)-specific ribonuclease PARN (PARN).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Poly(A)-specific ribonuclease PARN (PARN).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Poly(A)-specific ribonuclease PARN (PARN).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Poly(A)-specific ribonuclease PARN (PARN).	[22]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Poly(A)-specific ribonuclease PARN (PARN).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Poly(A)-specific ribonuclease PARN (PARN).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Poly(A)-specific ribonuclease PARN (PARN).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Poly(A)-specific ribonuclease PARN (PARN).	[26]

References

• [1] Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita. J Clin Invest. 2015 May;125(5):2151-60. doi: 10.1172/JCI78963. Epub 2015 Apr 20.
• [2] From incomplete penetrance with normal telomere length to severe disease and telomere shortening in a family with monoallelic and biallelic PARN pathogenic variants.Hum Mutat. 2019 Dec;40(12):2414-2429. doi: 10.1002/humu.23898. Epub 2019 Sep 15.
• [3] Alterations of deadenylase expression in acute leukemias: evidence for poly(a)-specific ribonuclease as a potential biomarker.Acta Haematol. 2012;128(1):39-46. doi: 10.1159/000337418. Epub 2012 May 17.
• [4] Nuclear Tau, p53 and Pin1 Regulate PARN-Mediated Deadenylation and Gene Expression.Front Mol Neurosci. 2019 Oct 15;12:242. doi: 10.3389/fnmol.2019.00242. eCollection 2019.
• [5] A feedback mechanism between PLD and deadenylase PARN for the shortening of eukaryotic poly(A) mRNA tails that is deregulated in cancer cells.Biol Open. 2017 Feb 15;6(2):176-186. doi: 10.1242/bio.021261.
• [6] Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive.Eur Respir J. 2016 Dec;48(6):1710-1720. doi: 10.1183/13993003.00308-2016. Epub 2016 Aug 18.
• [7] Dive Risk Factors, Gas Bubble Formation, and Decompression Illness in Recreational SCUBA Diving: Analysis of DAN Europe DSL Data Base.Front Psychol. 2017 Sep 19;8:1587. doi: 10.3389/fpsyg.2017.01587. eCollection 2017.
• [8] Divergent functional connectivity during attentional processing in Lewy body dementia and Alzheimer's disease.Cortex. 2017 Jul;92:8-18. doi: 10.1016/j.cortex.2017.02.016. Epub 2017 Mar 18.
• [9] Poly(A)-specific ribonuclease and Nocturnin in squamous cell lung cancer: prognostic value and impact on gene expression.Mol Cancer. 2015 Nov 5;14:187. doi: 10.1186/s12943-015-0457-3.
• [10] Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN).J Med Genet. 2015 Nov;52(11):738-48. doi: 10.1136/jmedgenet-2015-103292. Epub 2015 Sep 4.
• [11] k-RAS mutation and resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment in patients with nonsmall cell lung cancer.J Cancer Res Ther. 2017;13(4):699-701. doi: 10.4103/jcrt.JCRT_468_17.
• [12] Lung Transplant Outcomes in Patients With Pulmonary Fibrosis With Telomere-Related Gene Variants.Chest. 2019 Sep;156(3):477-485. doi: 10.1016/j.chest.2019.03.030. Epub 2019 Apr 9.
• [13] Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat Genet. 2015 May;47(5):512-7. doi: 10.1038/ng.3278. Epub 2015 Apr 13.
• [14] Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study.Ann Intern Med. 2018 Jan 16;168(2):100-109. doi: 10.7326/M17-1319. Epub 2017 Dec 5.
• [15] Impaired telomere integrity and rRNA biogenesis in PARN-deficient patients and knock-out models.EMBO Mol Med. 2019 Jul;11(7):e10201. doi: 10.15252/emmm.201810201. Epub 2019 Jun 6.
• [16] Synthesis and Preliminary Cytotoxicity Studies of 1-[1-(4,5-Dihydrooxazol- 2-yl)-1H-indazol-3-yl]-3-phenylurea and 3-phenylthiourea Derivatives.Med Chem. 2017;13(7):616-624. doi: 10.2174/1573406413666170306114401.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [21] 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.
• [22] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.