Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE262KF)

• DOT Name: Gem-associated protein 6 (GEMIN6)
• Synonyms: Gemin-6; SIP2
• Gene Name: GEMIN6
• Related Disease:
  Motor neurone disease
  Spinal muscular atrophy
  Amyotrophic lateral sclerosis
• UniProt ID: GEMI6_HUMAN
• PDB ID: 1Y96; 7BBL
• Pfam ID: PF06372 ; PF20417
• Sequence:
  MSEWMKKGPLEWQDYIYKEVRVTASEKNEYKGWVLTTDPVSANIVLVNFLEDGSMSVTGI
  MGHAVQTVETMNEGDHRVREKLMHLFTSGDCKAYSPEDLEERKNSLKKWLEKNHIPITEQ
  GDAPRTLCVAGVLTIDPPYGPENCSSSNEIILSRVQDLIEGHLTASQ
• Function: The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs. Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP. To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A forming an intermediate. Binding of snRNA inside 5Sm triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP.
• Reactome Pathway:
  SARS-CoV-2 modulates host translation machinery (R-HSA-9754678)
  snRNP Assembly (R-HSA-191859)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Motor neurone disease	DISUHWUI	Strong	Biomarker	[1]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Gem-associated protein 6 (GEMIN6).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Gem-associated protein 6 (GEMIN6).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Gem-associated protein 6 (GEMIN6).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gem-associated protein 6 (GEMIN6).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Gem-associated protein 6 (GEMIN6).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Gem-associated protein 6 (GEMIN6).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Gem-associated protein 6 (GEMIN6).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Gem-associated protein 6 (GEMIN6).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Gem-associated protein 6 (GEMIN6).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Gem-associated protein 6 (GEMIN6).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Gem-associated protein 6 (GEMIN6).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Gem-associated protein 6 (GEMIN6).	[17]

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 decreases the methylation of Gem-associated protein 6 (GEMIN6).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Gem-associated protein 6 (GEMIN6).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Gem-associated protein 6 (GEMIN6).	[16]

References

• [1] Gemins modulate the expression and activity of the SMN complex.Hum Mol Genet. 2005 Jun 15;14(12):1605-11. doi: 10.1093/hmg/ddi168. Epub 2005 Apr 20.
• [2] Sporadic amyotrophic lateral sclerosis: is SMN-Gemins protein complex of importance for the relative resistance of oculomotor nucleus motoneurons to degeneration?.Folia Neuropathol. 2018;56(4):308-320. doi: 10.5114/fn.2018.80864.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.