Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN0K7F3)

• DOT Name: Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2)
• Synonyms: Eukaryotic peptide chain release factor subunit 3b; eRF3b; EC 3.6.5.-; G1 to S phase transition protein 2 homolog
• Gene Name: GSPT2
• Related Disease:
  Intellectual disability
  B-cell neoplasm
  Liver cirrhosis
  Gastric cancer
  Stomach cancer
• UniProt ID: ERF3B_HUMAN
• PDB ID: 3KUJ
• EC Number: 3.6.5.-
• Pfam ID: PF00009 ; PF03144 ; PF03143 ; PF07145
• Sequence:
  MDSGSSSSDSAPDCWDQVDMESPGSAPSGDGVSSAVAEAQREPLSSAFSRKLNVNAKPFV
  PNVHAAEFVPSFLRGPTQPPTLPAGSGSNDETCTGAGYPQGKRMGRGAPVEPSREEPLVS
  LEGSNSAVTMELSEPVVENGEVEMALEESWEHSKEVSEAEPGGGSSGDSGPPEESGQEMM
  EEKEEIRKSKSVIVPSGAPKKEHVNVVFIGHVDAGKSTIGGQIMFLTGMVDKRTLEKYER
  EAKEKNRETWYLSWALDTNQEERDKGKTVEVGRAYFETERKHFTILDAPGHKSFVPNMIG
  GASQADLAVLVISARKGEFETGFEKGGQTREHAMLAKTAGVKHLIVLINKMDDPTVNWSI
  ERYEECKEKLVPFLKKVGFSPKKDIHFMPCSGLTGANIKEQSDFCPWYTGLPFIPYLDNL
  PNFNRSIDGPIRLPIVDKYKDMGTVVLGKLESGSIFKGQQLVMMPNKHNVEVLGILSDDT
  ETDFVAPGENLKIRLKGIEEEEILPGFILCDPSNLCHSGRTFDVQIVIIEHKSIICPGYN
  AVLHIHTCIEEVEITALISLVDKKSGEKSKTRPRFVKQDQVCIARLRTAGTICLETFKDF
  PQMGRFTLRDEGKTIAIGKVLKLVPEKD
• Function: GTPase component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons UAA, UAG and UGA. GSPT2/ERF3B mediates ETF1/ERF1 delivery to stop codons: The eRF1-eRF3-GTP complex binds to a stop codon in the ribosomal A-site. GTP hydrolysis by GSPT2/ERF3B induces a conformational change that leads to its dissociation, permitting ETF1/ERF1 to accommodate fully in the A-site. Component of the transient SURF complex which recruits UPF1 to stalled ribosomes in the context of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons.
• Tissue Specificity: Highly expressed in IUCC stage II colorectal cancer (CRC).
• KEGG Pathway: mR. surveillance pathway (hsa03015)
• Reactome Pathway:
  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)
  Eukaryotic Translation Termination (R-HSA-72764)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Biomarker	[1]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[2]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Limited	Biomarker	[3]
Stomach cancer	DISKIJSX	Limited	Biomarker	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2) affects the response to substance of Topotecan.	[13]

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 Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2).	[12]

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 increases the methylation of Eukaryotic peptide chain release factor GTP-binding subunit ERF3B (GSPT2).	[9]

References

• [1] Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability.PLoS One. 2017 Apr 17;12(4):e0175962. doi: 10.1371/journal.pone.0175962. eCollection 2017.
• [2] eRF3b-37 inhibits the TGF-1-induced activation of hepatic stellate cells by regulating cell proliferation, G0/G1 arrest, apoptosis and migration.Int J Mol Med. 2018 Dec;42(6):3602-3612. doi: 10.3892/ijmm.2018.3900. Epub 2018 Sep 26.
• [3] Combination of TNM staging and pathway based risk score models in patients with gastric cancer.J Cell Biochem. 2018 Apr;119(4):3608-3617. doi: 10.1002/jcb.26563. Epub 2018 Jan 9.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] 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.
• [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] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [11] 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.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [13] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.