Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGVT0SH)

• DOT Name: Trinucleotide repeat-containing gene 6B protein (TNRC6B)
• Gene Name: TNRC6B
• Related Disease:
  Complex neurodevelopmental disorder
  Neurodevelopmental disorder
  Breast carcinoma
  Esophageal squamous cell carcinoma
  Global developmental delay with speech and behavioral abnormalities
  Leiomyoma
  Nasopharyngeal carcinoma
  Polycystic ovarian syndrome
  Prostate cancer
  Prostate carcinoma
  Respiratory failure
  Uterine fibroids
  Small lymphocytic lymphoma
  Syndromic intellectual disability
• UniProt ID: TNR6B_HUMAN
• Pfam ID: PF10427 ; PF16608
• Sequence:
  MREKEQEREEQLMEDKKRKKEDKKKKEATQKVTEQKTKVPEVTKPSLSQPTAASPIGSSP
  SPPVNGGNNAKRVAVPNGQPPSAARYMPREVPPRFRCQQDHKVLLKRGQPPPPSCMLLGG
  GAGPPPCTAPGANPNNAQVTGALLQSESGTAPDSTLGGAAASNYANSTWGSGASSNNGTS
  PNPIHIWDKVIVDGSDMEEWPCIASKDTESSSENTTDNNSASNPGSEKSTLPGSTTSNKG
  KGSQCQSASSGNECNLGVWKSDPKAKSVQSSNSTTENNNGLGNWRNVSGQDRIGPGSGFS
  NFNPNSNPSAWPALVQEGTSRKGALETDNSNSSAQVSTVGQTSREQQSKMENAGVNFVVS
  GREQAQIHNTDGPKNGNTNSLNLSSPNPMENKGMPFGMGLGNTSRSTDAPSQSTGDRKTG
  SVGSWGAARGPSGTDTVSGQSNSGNNGNNGKEREDSWKGASVQKSTGSKNDSWDNNNRST
  GGSWNFGPQDSNDNKWGEGNKMTSGVSQGEWKQPTGSDELKIGEWSGPNQPNSSTGAWDN
  QKGHPLPENQGNAQAPCWGRSSSSTGSEVGGQSTGSNHKAGSSDSHNSGRRSYRPTHPDC
  QAVLQTLLSRTDLDPRVLSNTGWGQTQIKQDTVWDIEEVPRPEGKSDKGTEGWESAATQT
  KNSGGWGDAPSQSNQMKSGWGELSASTEWKDPKNTGGWNDYKNNNSSNWGGGRPDEKTPS
  SWNENPSKDQGWGGGRQPNQGWSSGKNGWGEEVDQTKNSNWESSASKPVSGWGEGGQNEI
  GTWGNGGNASLASKGGWEDCKRSPAWNETGRQPNSWNKQHQQQQPPQQPPPPQPEASGSW
  GGPPPPPPGNVRPSNSSWSSGPQPATPKDEEPSGWEEPSPQSISRKMDIDDGTSAWGDPN
  SYNYKNVNLWDKNSQGGPAPREPNLPTPMTSKSASVWSKSTPPAPDNGTSAWGEPNESSP
  GWGEMDDTGASTTGWGNTPANAPNAMKPNSKSMQDGWGESDGPVTGARHPSWEEEEDGGV
  WNTTGSQGSASSHNSASWGQGGKKQMKCSLKGGNNDSWMNPLAKQFSNMGLLSQTEDNPS
  SKMDLSVGSLSDKKFDVDKRAMNLGDFNDIMRKDRSGFRPPNSKDMGTTDSGPYFEKLTL
  PFSNQDGCLGDEAPCSPFSPSPSYKLSPSGSTLPNVSLGAIGTGLNPQNFAARQGGSHGL
  FGNSTAQSRGLHTPVQPLNSSPSLRAQVPPQFISPQVSASMLKQFPNSGLSPGLFNVGPQ
  LSPQQIAMLSQLPQIPQFQLACQLLLQQQQQQQLLQNQRKISQAVRQQQEQQLARMVSAL
  QQQQQQQQRQPGMKHSPSHPVGPKPHLDNMVPNALNVGLPDLQTKGPIPGYGSGFSSGGM
  DYGMVGGKEAGTESRFKQWTSMMEGLPSVATQEANMHKNGAIVAPGKTRGGSPYNQFDII
  PGDTLGGHTGPAGDSWLPAKSPPTNKIGSKSSNASWPPEFQPGVPWKGIQNIDPESDPYV
  TPGSVLGGTATSPIVDTDHQLLRDNTTGSNSSLNTSLPSPGAWPYSASDNSFTNVHSTSA
  KFPDYKSTWSPDPIGHNPTHLSNKMWKNHISSRNTTPLPRPPPGLTNPKPSSPWSSTAPR
  SVRGWGTQDSRLASASTWSDGGSVRPSYWLVLHNLTPQIDGSTLRTICMQHGPLLTFHLN
  LTQGTALIRYSTKQEAAKAQTALHMCVLGNTTILAEFATDDEVSRFLAQAQPPTPAATPS
  APAAGWQSLETGQNQSDPVGPALNLFGGSTGLGQWSSSAGGSSGADLAGASLWGPPNYSS
  SLWGVPTVEDPHRMGSPAPLLPGDLLGGGSDSI
• Function: Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs). Required for miRNA-dependent translational repression and siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins. As scaffolding protein associates with argonaute proteins bound to partially complementary mRNAs and simultaneously can recruit CCR4-NOT and PAN deadenylase complexes.
• Reactome Pathway:
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Oncogene Induced Senescence (R-HSA-2559585)
  Ca2+ pathway (R-HSA-4086398)
  Post-transcriptional silencing by small RNAs (R-HSA-426496)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Transcriptional Regulation by VENTX (R-HSA-8853884)
  Regulation of RUNX1 Expression and Activity (R-HSA-8934593)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  Regulation of PTEN mRNA translation (R-HSA-8943723)
  Competing endogenous RNAs (ceRNAs) regulate PTEN translation (R-HSA-8948700)
  Transcriptional Regulation by MECP2 (R-HSA-8986944)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  Regulation of CDH11 mRNA translation by microRNAs (R-HSA-9759811)
  Regulation of NPAS4 mRNA translation (R-HSA-9768778)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[4]
Global developmental delay with speech and behavioral abnormalities	DISE1NJQ	Strong	Autosomal dominant	[5]
Leiomyoma	DISLDDFN	Strong	Genetic Variation	[6]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[7]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[10]
Respiratory failure	DISVMYJO	Strong	Biomarker	[11]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[12]
Small lymphocytic lymphoma	DIS30POX	moderate	Genetic Variation	[13]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[14]

13 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 Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[20]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[21]
Marinol	DM70IK5	Approved	Marinol increases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[22]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[24]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Trinucleotide repeat-containing gene 6B protein (TNRC6B).	[28]

References

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• [2] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [3] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [4] Genetic polymorphisms of microRNA machinery genes predict overall survival of esophageal squamous carcinoma.J Clin Lab Anal. 2018 Jan;32(1):e22170. doi: 10.1002/jcla.22170. Epub 2017 Dec 11.
• [5] Evaluation of GWAS candidate susceptibility loci for uterine leiomyoma in the multi-ethnic NIEHS uterine fibroid study. Front Genet. 2015 Jul 14;6:241. doi: 10.3389/fgene.2015.00241. eCollection 2015.
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• [10] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [11] Trinucleotide repeat containing 6c (TNRC6c) is essential for microvascular maturation during distal airspace sacculation in the developing lung.Dev Biol. 2017 Oct 1;430(1):214-223. doi: 10.1016/j.ydbio.2017.07.018. Epub 2017 Aug 12.
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• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [20] 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.
• [21] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
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• [23] 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.
• [24] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [25] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
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• [27] 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.
• [28] 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.