Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT493IOM)

• DOT Name: Trinucleotide repeat-containing gene 6A protein (TNRC6A)
• Synonyms: CAG repeat protein 26; EMSY interactor protein; GW182 autoantigen; Protein GW1; Glycine-tryptophan protein of 182 kDa
• Gene Name: TNRC6A
• Related Disease:
  Autoimmune disease
  Advanced cancer
  Alzheimer disease
  Benign adult familial myoclonic epilepsy
  Dravet syndrome
  Esophageal cancer
  Familial infantile myoclonic epilepsy
  Hepatitis C virus infection
  Myocardial infarction
  Myoclonic-astatic epilepsy
  Acute myelogenous leukaemia
  Kaposi sarcoma
  Breast cancer
  Breast carcinoma
  Chronic obstructive pulmonary disease
  Colorectal carcinoma
  Epilepsy, familial adult myoclonic, 6
  Gastric cancer
  Psychotic disorder
• UniProt ID: TNR6A_HUMAN
• PDB ID: 5W6V; 7RUP
• Pfam ID: PF10427 ; PF16608
• Sequence:
  MRELEAKATKDVERNLSRDLVQEEEQLMEEKKKKKDDKKKKEAAQKKATEQKIKVPEQIK
  PSVSQPQPANSNNGTSTATSTNNNAKRATANNQQPQQQQQQQQPQQQQPQQQPQPQPQQQ
  QPQQQPQALPRYPREVPPRFRHQEHKQLLKRGQHFPVIAANLGSAVKVLNSQSESSALTN
  QQPQNNGEVQNSKNQSDINHSTSGSHYENSQRGPVSSTSDSSTNCKNAVVSDLSEKEAWP
  SAPGSDPELASECMDADSASSSESERNITIMASGNTGGEKDGLRNSTGLGSQNKFVVGSS
  SNNVGHGSSTGPWGFSHGAIISTCQVSVDAPESKSESSNNRMNAWGTVSSSSNGGLNPST
  LNSASNHGAWPVLENNGLALKGPVGSGSSGINIQCSTIGQMPNNQSINSKVSGGSTHGTW
  GSLQETCESEVSGTQKVSFSGQPQNITTEMTGPNNTTNFMTSSLPNSGSVQNNELPSSNT
  GAWRVSTMNHPQMQAPSGMNGTSLSHLSNGESKSGGSYGTTWGAYGSNYSGDKCSGPNGQ
  ANGDTVNATLMQPGVNGPMGTNFQVNTNKGGGVWESGAANSQSTSWGSGNGANSGGSRRG
  WGTPAQNTGTNLPSVEWNKLPSNQHSNDSANGNGKTFTNGWKSTEEEDQGSATSQTNEQS
  SVWAKTGGTVESDGSTESTGRLEEKGTGESQSRDRRKIDQHTLLQSIVNRTDLDPRVLSN
  SGWGQTPIKQNTAWDTETSPRGERKTDNGTEAWGSSATQTFNSGACIDKTSPNGNDTSSV
  SGWGDPKPALRWGDSKGSNCQGGWEDDSAATGMVKSNQWGNCKEEKAAWNDSQKNKQGWG
  DGQKSSQGWSVSASDNWGETSRNNHWGEANKKSSSGGSDSDRSVSGWNELGKTSSFTWGN
  NINPNNSSGWDESSKPTPSQGWGDPPKSNQSLGWGDSSKPVSSPDWNKQQDIVGSWGIPP
  ATGKPPGTGWLGGPIPAPAKEEEPTGWEEPSPESIRRKMEIDDGTSAWGDPSKYNYKNVN
  MWNKNVPNGNSRSDQQAQVHQLLTPASAISNKEASSGSGWGEPWGEPSTPATTVDNGTSA
  WGKPIDSGPSWGEPIAAASSTSTWGSSSVGPQALSKSGPKSMQDGWCGDDMPLPGNRPTG
  WEEEEDVEIGMWNSNSSQELNSSLNWPPYTKKMSSKGLSGKKRRRERGMMKGGNKQEEAW
  INPFVKQFSNISFSRDSPEENVQSNKMDLSGGMLQDKRMEIDKHSLNIGDYNRTVGKGPG
  SRPQISKESSMERNPYFDKDGIVADESQNMQFMSSQSMKLPPSNSALPNQALGSIAGLGM
  QNLNSVRQNGNPSMFGVGNTAAQPRGMQQPPAQPLSSSQPNLRAQVPPPLLSPQVPVSLL
  KYAPNNGGLNPLFGPQQVAMLNQLSQLNQLSQISQLQRLLAQQQRAQSQRSVPSGNRPQQ
  DQQGRPLSVQQQMMQQSRQLDPNLLVKQQTPPSQQQPLHQPAMKSFLDNVMPHTTPELQK
  GPSPINAFSNFPIGLNSNLNVNMDMNSIKEPQSRLRKWTTVDSISVNTSLDQNSSKHGAI
  SSGFRLEESPFVPYDFMNSSTSPASPPGSIGDGWPRAKSPNGSSSVNWPPEFRPGEPWKG
  YPNIDPETDPYVTPGSVINNLSINTVREVDHLRDRNSGSSSSLNTTLPSTSAWSSIRASN
  YNVPLSSTAQSTSARNSDSKLTWSPGSVTNTSLAHELWKVPLPPKNITAPSRPPPGLTGQ
  KPPLSTWDNSPLRIGGGWGNSDARYTPGSSWGESSSGRITNWLVLKNLTPQIDGSTLRTL
  CMQHGPLITFHLNLPHGNALVRYSSKEEVVKAQKSLHMCVLGNTTILAEFASEEEISRFF
  AQSQSLTPSPGWQSLGSSQSRLGSLDCSHSFSSRTDLNHWNGAGLSGTNCGDLHGTSLWG
  TPHYSTSLWGPPSSSDPRGISSPSPINAFLSVDHLGGGGESM
• Function: Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs). Required for miRNA-dependent repression of translation and for siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins. As a scaffolding protein, associates with argonaute proteins bound to partially complementary mRNAs, and can simultaneously recruit CCR4-NOT and PAN deadenylase complexes.
• Tissue Specificity: Ubiquitous.
• 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)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  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

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Benign adult familial myoclonic epilepsy	DISIMWOV	Strong	Biomarker	[4]
Dravet syndrome	DISJF7LY	Strong	Biomarker	[4]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[5]
Familial infantile myoclonic epilepsy	DISELJ0F	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[7]
Myoclonic-astatic epilepsy	DISTAVMU	Strong	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[8]
Kaposi sarcoma	DISC1H1Z	Disputed	Biomarker	[9]
Breast cancer	DIS7DPX1	Limited	Biomarker	[10]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[10]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Genetic Variation	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[12]
Epilepsy, familial adult myoclonic, 6	DISK65YI	Limited	Unknown	[4]
Gastric cancer	DISXGOUK	Limited	Biomarker	[12]
Psychotic disorder	DIS4UQOT	Limited	Genetic Variation	[13]

9 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 6A protein (TNRC6A).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Trinucleotide repeat-containing gene 6A protein (TNRC6A).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Trinucleotide repeat-containing gene 6A protein (TNRC6A).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Trinucleotide repeat-containing gene 6A protein (TNRC6A).	[17]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Trinucleotide repeat-containing gene 6A protein (TNRC6A).	[18]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Trinucleotide repeat-containing gene 6A protein (TNRC6A).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Trinucleotide repeat-containing gene 6A protein (TNRC6A).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Trinucleotide repeat-containing gene 6A protein (TNRC6A).	[23]
Manganese	DMKT129	Investigative	Manganese increases the expression of Trinucleotide repeat-containing gene 6A protein (TNRC6A).	[24]

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 affects the methylation of Trinucleotide repeat-containing gene 6A protein (TNRC6A).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Trinucleotide repeat-containing gene 6A protein (TNRC6A).	[22]

References

• [1] An SNP in the trinucleotide repeat region of the TNRC6A gene maps to a major TNGW1 autoepitope in patients with autoantibodies to GW182.Adv Exp Med Biol. 2013;768:243-59. doi: 10.1007/978-1-4614-5107-5_14.
• [2] miR-30 disrupts senescence and promotes cancer by targeting both p16(INK4A) and DNA damage pathways.Oncogene. 2018 Oct;37(42):5618-5632. doi: 10.1038/s41388-018-0358-1. Epub 2018 Jun 15.
• [3] Genome-wide association study of the rate of cognitive decline in Alzheimer's disease.Alzheimers Dement. 2014 Jan;10(1):45-52. doi: 10.1016/j.jalz.2013.01.008. Epub 2013 Mar 25.
• [4] Expansions?of?intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat Genet. 2018 Apr;50(4):581-590. doi: 10.1038/s41588-018-0067-2. Epub 2018 Mar 5.
• [5] Immunohistochemical analysis of RNA-induced silencing complex-related proteins AGO2 and TNRC6A in prostate and esophageal cancers.APMIS. 2010 Apr;118(4):271-6. doi: 10.1111/j.1600-0463.2010.02588.x.
• [6] TNRC6 proteins modulate hepatitis C virus replication by spatially regulating the binding of miR-122/Ago2 complexes to viral RNA.Nucleic Acids Res. 2019 Jul 9;47(12):6411-6424. doi: 10.1093/nar/gkz278.
• [7] Aberrant expression of TNRC6a and miR-21 during myocardial infarction.3 Biotech. 2019 Jul;9(7):285. doi: 10.1007/s13205-019-1812-7. Epub 2019 Jun 25.
• [8] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [9] KSHV RNA-binding protein ORF57 inhibits P-body formation to promote viral multiplication by interaction with Ago2 and GW182.Nucleic Acids Res. 2019 Sep 26;47(17):9368-9385. doi: 10.1093/nar/gkz683.
• [10] RIP-Chip analysis supports different roles for AGO2 and GW182 proteins in recruiting and processing microRNA targets.BMC Bioinformatics. 2019 Apr 18;20(Suppl 4):120. doi: 10.1186/s12859-019-2683-y.
• [11] Genetic overlap of chronic obstructive pulmonary disease and cardiovascular disease-related traits: a large-scale genome-wide cross-trait analysis.Respir Res. 2019 Apr 2;20(1):64. doi: 10.1186/s12931-019-1036-8.
• [12] Somatic mutations and losses of expression of microRNA regulation-related genes AGO2 and TNRC6A in gastric and colorectal cancers.J Pathol. 2010 Jun;221(2):139-46. doi: 10.1002/path.2683.
• [13] Sleep duration and psychotic experiences in patients at risk of psychosis: A secondary analysis of the EDIE-2 trial.Schizophr Res. 2019 Feb;204:326-333. doi: 10.1016/j.schres.2018.08.006. Epub 2018 Aug 16.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] 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.
• [17] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [18] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [19] 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.
• [20] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [24] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.