Details of Drug Off-Target (DOT)

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

• DOT Name: Telomerase-binding protein EST1A (SMG6)
• Synonyms: EC 3.1.-.-; Ever shorter telomeres 1A; hEST1A; Nonsense mediated mRNA decay factor SMG6; Smg-6 homolog; hSmg5/7a
• Gene Name: SMG6
• Related Disease:
  Epilepsy
  Knee osteoarthritis
  Lissencephaly spectrum disorders
  Neoplasm
  Schizophrenia
  Temporal lobe epilepsy
  Venous thromboembolism
  Coronary heart disease
  Mitral valve prolapse
  Neoplasm of esophagus
  Squamous cell carcinoma
• UniProt ID: EST1A_HUMAN
• PDB ID: 2DOK; 2HWW; 2HWX; 4UM2
• EC Number: 3.1.-.-
• Pfam ID: PF10374 ; PF10373 ; PF13638
• Sequence:
  MAEGLERVRISASELRGILATLAPQAGSRENMKELKEARPRKDNRRPDLEIYKPGLSRLR
  NKPKIKEPPGSEEFKDEIVNDRDCSAVENGTQPVKDVCKELNNQEQNGPIDPENNRGQES
  FPRTAGQEDRSLKIIKRTKKPDLQIYQPGRRLQTVSKESASRVEEEEVLNQVEQLRVEED
  ECRGNVAKEEVANKPDRAEIEKSPGGGRVGAAKGEKGKRMGKGEGVRETHDDPARGRPGS
  AKRYSRSDKRRNRYRTRSTSSAGSNNSAEGAGLTDNGCRRRRQDRTKERPRLKKQVSVSS
  TDSLDEDRIDEPDGLGPRRSSERKRHLERNWSGRGEGEQKNSAKEYRGTLRVTFDAEAMN
  KESPMVRSARDDMDRGKPDKGLSSGGKGSEKQESKNPKQELRGRGRGILILPAHTTLSVN
  SAGSPESAPLGPRLLFGSGSKGSRSWGRGGTTRRLWDPNNPDQKPALKTQTPQLHFLDTD
  DEVSPTSWGDSRQAQASYYKFQNSDNPYYYPRTPGPASQYPYTGYNPLQYPVGPTNGVYP
  GPYYPGYPTPSGQYVCSPLPTSTMSPEEVEQHMRNLQQQELHRLLRVADNQELQLSNLLS
  RDRISPEGLEKMAQLRAELLQLYERCILLDIEFSDNQNVDQILWKNAFYQVIEKFRQLVK
  DPNVENPEQIRNRLLELLDEGSDFFDSLLQKLQVTYKFKLEDYMDGLAIRSKPLRKTVKY
  ALISAQRCMICQGDIARYREQASDTANYGKARSWYLKAQHIAPKNGRPYNQLALLAVYTR
  RKLDAVYYYMRSLAASNPILTAKESLMSLFEETKRKAEQMEKKQHEEFDLSPDQWRKGKK
  STFRHVGDDTTRLEIWIHPSHPRSSQGTESGKDSEQENGLGSLSPSDLNKRFILSFLHAH
  GKLFTRIGMETFPAVAEKVLKEFQVLLQHSPSPIGSTRMLQLMTINMFAVHNSQLKDCFS
  EECRSVIQEQAAALGLAMFSLLVRRCTCLLKESAKAQLSSPEDQDDQDDIKVSSFVPDLK
  ELLPSVKVWSDWMLGYPDTWNPPPTSLDLPSHVAVDVWSTLADFCNILTAVNQSEVPLYK
  DPDDDLTLLILEEDRLLSGFVPLLAAPQDPCYVEKTSDKVIAADCKRVTVLKYFLEALCG
  QEEPLLAFKGGKYVSVAPVPDTMGKEMGSQEGTRLEDEEEDVVIEDFEEDSEAEGSGGED
  DIRELRAKKLALARKIAEQQRRQEKIQAVLEDHSQMRQMELEIRPLFLVPDTNGFIDHLA
  SLARLLESRKYILVVPLIVINELDGLAKGQETDHRAGGYARVVQEKARKSIEFLEQRFES
  RDSCLRALTSRGNELESIAFRSEDITGQLGNNDDLILSCCLHYCKDKAKDFMPASKEEPI
  RLLREVVLLTDDRNLRVKALTRNVPVRDIPAFLTWAQVG
• Function: Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini. May have a general role in telomere regulation. Promotes in vitro the ability of TERT to elongate telomeres. Overexpression induces telomere uncapping, chromosomal end-to-end fusions (telomeric DNA persists at the fusion points) and did not perturb TRF2 telomeric localization. Binds to the single-stranded 5'-(GTGTGG)(4)GTGT-3' telomeric DNA, but not to a telomerase RNA template component (TER) ; Plays a role in nonsense-mediated mRNA decay. Is thought to provide a link to the mRNA degradation machinery as it has endonuclease activity required to initiate NMD, and to serve as an adapter for UPF1 to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation. Degrades single-stranded RNA (ssRNA), but not ssDNA or dsRNA.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: mR. surveillance pathway (hsa03015)
• Reactome Pathway: Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Strong	Genetic Variation	[1]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[2]
Lissencephaly spectrum disorders	DISBCZL7	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Temporal lobe epilepsy	DISNOPXX	Strong	Genetic Variation	[1]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[5]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[6]
Mitral valve prolapse	DISNCHQ3	Limited	Genetic Variation	[7]
Neoplasm of esophagus	DISOLKAQ	Limited	Genetic Variation	[8]
Squamous cell carcinoma	DISQVIFL	Limited	Genetic Variation	[8]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Telomerase-binding protein EST1A (SMG6).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Telomerase-binding protein EST1A (SMG6).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Telomerase-binding protein EST1A (SMG6).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Telomerase-binding protein EST1A (SMG6).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Telomerase-binding protein EST1A (SMG6).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Telomerase-binding protein EST1A (SMG6).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Telomerase-binding protein EST1A (SMG6).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Telomerase-binding protein EST1A (SMG6).	[13]
Marinol	DM70IK5	Approved	Marinol increases the expression of Telomerase-binding protein EST1A (SMG6).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Telomerase-binding protein EST1A (SMG6).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Telomerase-binding protein EST1A (SMG6).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Telomerase-binding protein EST1A (SMG6).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Telomerase-binding protein EST1A (SMG6).	[19]

References

• [1] SRR intronic variation inhibits expression of its neighbouring SMG6 gene and protects against temporal lobe epilepsy.J Cell Mol Med. 2018 Mar;22(3):1883-1893. doi: 10.1111/jcmm.13473. Epub 2018 Jan 24.
• [2] Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019 Feb;51(2):230-236.
• [3] Evidence for association between structural variants in lissencephaly-related genes and executive deficits in schizophrenia or bipolar patients from a Spanish isolate population.Psychiatr Genet. 2008 Dec;18(6):313-7. doi: 10.1097/YPG.0b013e3283118725.
• [4] Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.Nat Genet. 2018 Mar;50(3):381-389. doi: 10.1038/s41588-018-0059-2. Epub 2018 Feb 26.
• [5] Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
• [6] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [7] Genetic association analyses highlight biological pathways underlying mitral valve prolapse.Nat Genet. 2015 Oct;47(10):1206-11. doi: 10.1038/ng.3383. Epub 2015 Aug 24.
• [8] Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.Nat Genet. 2012 Oct;44(10):1090-7. doi: 10.1038/ng.2411. Epub 2012 Sep 9.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] 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.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] 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.