Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY9PCZY)

• DOT Name: Nonsense-mediated mRNA decay factor SMG8 (SMG8)
• Synonyms: Amplified in breast cancer gene 2 protein; Protein smg-8 homolog
• Gene Name: SMG8
• Related Disease:
  Alzahrani-Kuwahara syndrome
  Brain cancer
  Brain neoplasm
  CARASIL syndrome
  Neoplasm
  Meningioma
• UniProt ID: SMG8_HUMAN
• PDB ID: 6L54; 6SYT; 6Z3R; 7PW4; 7PW5; 7PW8
• Pfam ID: PF10220
• Sequence:
  MAGPVSLRDLLMGASAWMGSESPGGSPTEGGGSAAGGPEPPWREDEICVVGIFGKTALRL
  NSEKFSLVNTVCDRQVFPLFRHQDPGDPGPGIRTEAGAVGEAGGAEDPGAAAGGSVRGSG
  AVAEGNRTEAGSQDYSLLQAYYSQESKVLYLLLTSICDNSQLLRACRALQSGEAGGGLSL
  PHAEAHEFWKHQEKLQCLSLLYLFSVCHILLLVHPTCSFDITYDRVFRALDGLRQKVLPL
  LKTAIKDCPVGKDWKLNCRPCPPRLLFLFQLNGALKVEPPRNQDPAHPDKPKKHSPKRRL
  QHALEDQIYRIFRKSRVLTNQSINCLFTVPANQAFVYIVPGSQEEDPVGMLLDQLRSHCT
  VKDPESLLVPAPLSGPRRYQVMRQHSRQQLSFHIDSSSSSSSGQLVDFTLREFLWQHVEL
  VLSKKGFDDSVGRNPQPSHFELPTYQKWISAASKLYEVAIDGKEEDLGSPTGELTSKILS
  SIKVLEGFLDIDTKFSENRCQKALPMAHSAYQSNLPHNYTMTVHKNQLAQALRVYSQHAR
  GPAFHKYAMQLHEDCYKFWSNGHQLCEERSLTDQHCVHKFHSLPKSGEKPEADRNPPVLY
  HNSRARSTGACNCGRKQAPRDDPFDIKAANYDFYQLLEEKCCGKLDHINFPVFEPSTPDP
  APAKNESSPAPPDSDADKLKEKEPQTQGESTSLSLALSLGQSTDSLGTYPADPQAGGDNP
  EVHGQVEVKTEKRPNFVDRQASTVEYLPGMLHSNCPKGLLPKFSSWSLVKLGPAKSYNFH
  TGLDQQGFIPGTNYLMPWDIVIRTRAEDEGDLDTNSWPAPNKAIPGKRSAVVMGRGRRRD
  DIARAFVGFEYEDSRGRRFMCSGPDKVMKVMGSGPKESALKALNSDMPLYILSSSQGRGL
  KPHYAQLMRLFVVVPDAPLQIILMPQVQPGPPPCPVFYPEKQEITLPPDGLWVLRFPYAY
  VTERGPCFPPKENVQLMSYKVLRGVLKAVTQ
• 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 SMG9 (forming the SMG1C protein kinase complex) and, in the SMG1C complex, is required to mediate the recruitment of SMG1 to the ribosome:SURF complex and to suppress SMG1 kinase activity until the ribosome:SURF complex locates the exon junction complex (EJC). Acts as a regulator of kinase activity.
• Reactome Pathway: Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzahrani-Kuwahara syndrome	DIS409BQ	Definitive	Autosomal recessive	[1]
Brain cancer	DISBKFB7	Strong	Biomarker	[2]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[2]
CARASIL syndrome	DIS7KGGR	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Meningioma	DISPT4TG	Limited	Biomarker	[5]

3 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 SMG8 (SMG8).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nonsense-mediated mRNA decay factor SMG8 (SMG8).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Nonsense-mediated mRNA decay factor SMG8 (SMG8).	[8]

2 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 Nonsense-mediated mRNA decay factor SMG8 (SMG8).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Nonsense-mediated mRNA decay factor SMG8 (SMG8).	[10]

References

• [1] 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.
• [2] Where are we now? And where are we going? A report from the Accelerate Brain Cancer Cure (ABC2) low-grade glioma research workshop.Neuro Oncol. 2014 Jan;16(2):173-8. doi: 10.1093/neuonc/not229. Epub 2013 Dec 4.
• [3] Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity.Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15037-42. doi: 10.1073/pnas.1300654110. Epub 2013 Aug 27.
• [4] Calculating the Tumor Volumes in Vestibular Schwannomas: Are the ABC/2 and Volumetric Methods Comparable?.Otol Neurotol. 2017 Jul;38(6):889-894. doi: 10.1097/MAO.0000000000001423.
• [5] Comparison of ABC/2 estimation and a volumetric computerized method for measurement of meningiomas using magnetic resonance imaging.J Neurooncol. 2019 Sep;144(2):275-282. doi: 10.1007/s11060-019-03205-z. Epub 2019 Aug 10.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [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] 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.