Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT172Y2R)

• DOT Name: Nonsense-mediated mRNA decay factor SMG9 (SMG9)
• Gene Name: SMG9
• Related Disease:
  Neoplasm
  Heart and brain malformation syndrome
• UniProt ID: SMG9_HUMAN
• PDB ID: 6L54; 6SYT; 6Z3R; 7PW4; 7PW5; 7PW7; 7PW8; 7PW9; 8FE7
• Sequence:
  MSESGHSQPGLYGIERRRRWKEPGSGGPQNLSGPGGRERDYIAPWERERRDASEETSTSV
  MQKTPIILSKPPAERSKQPPPPTAPAAPPAPAPLEKPIVLMKPREEGKGPVAVTGASTPE
  GTAPPPPAAPAPPKGEKEGQRPTQPVYQIQNRGMGTAAPAAMDPVVGQAKLLPPERMKHS
  IKLVDDQMNWCDSAIEYLLDQTDVLVVGVLGLQGTGKSMVMSLLSANTPEEDQRTYVFRA
  QSAEMKERGGNQTSGIDFFITQERIVFLDTQPILSPSILDHLINNDRKLPPEYNLPHTYV
  EMQSLQIAAFLFTVCHVVIVVQDWFTDLSLYRFLQTAEMVKPSTPSPSHESSSSSGSDEG
  TEYYPHLVFLQNKARREDFCPRKLRQMHLMIDQLMAHSHLRYKGTLSMLQCNVFPGLPPD
  FLDSEVNLFLVPFMDSEAESENPPRAGPGSSPLFSLLPGYRGHPSFQSLVSKLRSQVMSM
  ARPQLSHTILTEKNWFHYAARIWDGVRKSSALAEYSRLLA
• Function: Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Is recruited by release factors to stalled ribosomes together with SMG1 and SMG8 (forming the SMG1C protein kinase complex) and, in the SMG1C complex, is required for the efficient association between SMG1 and SMG8. Plays a role in brain, heart, and eye development.
• Reactome Pathway: Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Heart and brain malformation syndrome	DISVKL2V	Strong	Autosomal recessive	[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 Nonsense-mediated mRNA decay factor SMG9 (SMG9).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nonsense-mediated mRNA decay factor SMG9 (SMG9).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Nonsense-mediated mRNA decay factor SMG9 (SMG9).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nonsense-mediated mRNA decay factor SMG9 (SMG9).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Nonsense-mediated mRNA decay factor SMG9 (SMG9).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nonsense-mediated mRNA decay factor SMG9 (SMG9).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Nonsense-mediated mRNA decay factor SMG9 (SMG9).	[11]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Nonsense-mediated mRNA decay factor SMG9 (SMG9).	[12]

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 affects the methylation of Nonsense-mediated mRNA decay factor SMG9 (SMG9).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nonsense-mediated mRNA decay factor SMG9 (SMG9).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Nonsense-mediated mRNA decay factor SMG9 (SMG9).	[9]

References

• [1] Identification of novel gastric cancer-associated CNVs by integrated analysis of microarray.J Surg Oncol. 2010 Oct 1;102(5):454-61. doi: 10.1002/jso.21585.
• [2] Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice. Am J Hum Genet. 2016 Apr 7;98(4):643-52. doi: 10.1016/j.ajhg.2016.02.010. Epub 2016 Mar 24.
• [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] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] 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.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [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.
• [12] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.