Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC8MPTZ)

• DOT Name: 3'-5' exoribonuclease 1 (ERI1)
• Synonyms: EC 3.1.-.-; 3'-5' exonuclease ERI1; Eri-1 homolog; Histone mRNA 3'-end-specific exoribonuclease; Histone mRNA 3'-exonuclease 1; Protein 3'hExo; HEXO
• Gene Name: ERI1
• Related Disease:
  Narcolepsy
  Intellectual disability
• UniProt ID: ERI1_HUMAN
• PDB ID: 1W0H; 1ZBH; 1ZBU; 4L8R; 4QOZ
• EC Number: 3.1.-.-
• Pfam ID: PF00929 ; PF02037
• Sequence:
  MEDPQSKEPAGEAVALALLESPRPEGGEEPPRPSPEETQQCKFDGQETKGSKFITSSASD
  FSDPVYKEIAITNGCINRMSKEELRAKLSEFKLETRGVKDVLKKRLKNYYKKQKLMLKES
  NFADSYYDYICIIDFEATCEEGNPPEFVHEIIEFPVVLLNTHTLEIEDTFQQYVRPEINT
  QLSDFCISLTGITQDQVDRADTFPQVLKKVIDWMKLKELGTKYKYSLLTDGSWDMSKFLN
  IQCQLSRLKYPPFAKKWINIRKSYGNFYKVPRSQTKLTIMLEKLGMDYDGRPHCGLDDSK
  NIARIAVRMLQDGCELRINEKMHAGQLMSVSSSLPIEGTPPPQMPHFRK
• Function: RNA exonuclease that binds to the 3'-end of histone mRNAs and degrades them, suggesting that it plays an essential role in histone mRNA decay after replication. A 2' and 3'-hydroxyl groups at the last nucleotide of the histone 3'-end is required for efficient degradation of RNA substrates. Also able to degrade the 3'-overhangs of short interfering RNAs (siRNAs) in vitro, suggesting a possible role as regulator of RNA interference (RNAi). Required for binding the 5'-ACCCA-3' sequence present in stem-loop structure. Able to bind other mRNAs. Required for 5.8S rRNA 3'-end processing. Also binds to 5.8s ribosomal RNA. Binds with high affinity to the stem-loop structure of replication-dependent histone pre-mRNAs. In vitro, does not have sequence specificity. In vitro, has weak DNA exonuclease activity. In vitro, shows biphasic kinetics such that there is rapid hydrolysis of the last three unpaired RNA nucleotides in the 39 flanking sequence followed by a much slower cleavage through the stem that occurs over a longer incubation period in the order of hours.
• Reactome Pathway: Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[1]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[2]

8 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 3'-5' exoribonuclease 1 (ERI1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 3'-5' exoribonuclease 1 (ERI1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 3'-5' exoribonuclease 1 (ERI1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 3'-5' exoribonuclease 1 (ERI1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 3'-5' exoribonuclease 1 (ERI1).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of 3'-5' exoribonuclease 1 (ERI1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 3'-5' exoribonuclease 1 (ERI1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of 3'-5' exoribonuclease 1 (ERI1).	[11]

1 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 affects the methylation of 3'-5' exoribonuclease 1 (ERI1).	[9]

References

• [1] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [2] Homozygous microdeletion of the ERI1 and MFHAS1 genes in a patient with intellectual disability, limb abnormalities, and cardiac malformation.Am J Med Genet A. 2017 Jul;173(7):1955-1960. doi: 10.1002/ajmg.a.38271. Epub 2017 May 9.
• [3] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [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] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.