Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBR07PM)

• DOT Name: Trinucleotide repeat-containing gene 6C protein (TNRC6C)
• Gene Name: TNRC6C
• Related Disease:
  Cardiovascular disease
  Esophageal squamous cell carcinoma
  Hepatitis C virus infection
  Thyroid gland papillary carcinoma
• UniProt ID: TNR6C_HUMAN
• PDB ID: 2DKL; 2X04; 3KTP; 7RUQ
• Pfam ID: PF10427 ; PF12938 ; PF00076 ; PF16608 ; PF00627
• Sequence:
  MEEKKKKKQEEKKKKEGAQKKAADQKTKVPEPTKTCSSQPQPAGTSTSTSTSTISSSNNG
  KRASASGQQPAASRYLPREVPPRFRQQEQKQLLKRGQPLPTGTLTSVSPTQGAGPAGVSP
  PPLPGAGTQHHPSKLQPDLSHSGLADHYENSHWGQQPTYRSEANCSWDKVIIDRTDKEAW
  PSITGTETESASECTTDTDSASNCGSENSSMATGSAQGNFTGHTKKTNGNNGTNGALVQS
  PSNQSALGAGGANSNGSAARVWGVATGSSSGLAHCSVSGGDGKMDTMIGDGRSQNCWGAS
  NSNAGINLNLNPNANPAAWPVLGHEGTVATGNPSSICSPVSAIGQNMGNQNGNPTGTLGA
  WGNLLPQESTEPQTSTSQNVSFSAQPQNLNTDGPNNTNPMNSSPNPINAMQTNGLPNWGM
  AVGMGAIIPPHLQGLPGANGSSVSQVSGGSAEGISNSVWGLSPGNPATGNSNSGFSQGNG
  DTVNSALSAKQNGSSSAVQKEGSGGNAWDSGPPAGPGILAWGRGSGNNGVGNIHSGAWGH
  PSRSTSNGVNGEWGKPPNQHSNSDINGKGSTGWESPSVTSQNPTVQPGGEHMNSWAKAAS
  SGTTASEGSSDGSGNHNEGSTGREGTGEGRRRDKGIIDQGHIQLPRNDLDPRVLSNTGWG
  QTPVKQNTAWEFEESPRSERKNDNGTEAWGCAATQASNSGGKNDGSIMNSTNTSSVSGWV
  NAPPAAVPANTGWGDSNNKAPSGPGVWGDSISSTAVSTAAAAKSGHAWSGAANQEDKSPT
  WGEPPKPKSQHWGDGQRSNPAWSAGGGDWADSSSVLGHLGDGKKNGSGWDADSNRSGSGW
  NDTTRSGNSGWGNSTNTKANPGTNWGETLKPGPQQNWASKPQDNNVSNWGGAASVKQTGT
  GWIGGPVPVKQKDSSEATGWEEPSPPSIRRKMEIDDGTSAWGDPSNYNNKTVNMWDRNNP
  VIQSSTTTNTTTTTTTTTSNTTHRVETPPPHQAGTQLNRSPLLGPVSSGWGEMPNVHSKT
  ENSWGEPSSPSTLVDNGTAAWGKPPSSGSGWGDHPAEPPVAFGRAGAPVAASALCKPASK
  SMQEGWGSGGDEMNLSTSQWEDEEGDVWNNAASQESTSSCSSWGNAPKKGLQKGMKTSGK
  QDEAWIMSRLIKQLTDMGFPREPAEEALKSNNMNLDQAMSALLEKKVDVDKRGLGVTDHN
  GMAAKPLGCRPPISKESSVDRPTFLDKDGGLVEEPTPSPFLPSPSLKLPLSHSALPSQAL
  GGIASGLGMQNLNSSRQIPSGNLGMFGNSGAAQARTMQQPPQPPVQPLNSSQPSLRAQVP
  QFLSPQVQAQLLQFAAKNIGLNPALLTSPINPQHMTMLNQLYQLQLAYQRLQIQQQMLQA
  QRNVSGSMRQQEQQVARTITNLQQQIQQHQRQLAQALLVKQPPPPPPPPHLSLHPSAGKS
  AMDSFPSHPQTPGLPDLQTKEQQSSPNTFAPYPLAGLNPNMNVNSMDMTGGLSVKDPSQS
  QSRLPQWTHPNSMDNLPSAASPLEQNPSKHGAIPGGLSIGPPGKSSIDDSYGRYDLIQNS
  ESPASPPVAVPHSWSRAKSDSDKISNGSSINWPPEFHPGVPWKGLQNIDPENDPDVTPGS
  VPTGPTINTTIQDVNRYLLKSGGSSPPSSQNATLPSSSAWPLSASGYSSSFSSIASAPSV
  AGKLSDIKSTWSSGPTSHTQASLSHELWKVPRNSTAPTRPPPGLTNPKPSSTWGASPLGW
  TSSYSSGSAWSTDTSGRTSSWLVLRNLTPQIDGSTLRTLCLQHGPLITFHLNLTQGNAVV
  RYSSKEEAAKAQKSLHMCVLGNTTILAEFAGEEEVNRFLAQGQALPPTSSWQSSSASSQP
  RLSAAGSSHGLVRSDAGHWNAPCLGGKGSSELLWGGVPQYSSSLWGPPSADDSRVIGSPT
  PLTTLLPGDLLSGESL
• Function: Plays a role in RNA-mediated gene silencing by micro-RNAs (miRNAs). Required for miRNA-dependent translational repression of complementary mRNAs by argonaute family proteins. As scaffoldng 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[3]
Thyroid gland papillary carcinoma	DIS48YMM	Disputed	Altered Expression	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Trinucleotide repeat-containing gene 6C protein (TNRC6C) increases the Metabolic disorder ADR of Chlorothiazide.	[14]

8 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 6C protein (TNRC6C).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Trinucleotide repeat-containing gene 6C protein (TNRC6C).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Trinucleotide repeat-containing gene 6C protein (TNRC6C).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Trinucleotide repeat-containing gene 6C protein (TNRC6C).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Trinucleotide repeat-containing gene 6C protein (TNRC6C).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Trinucleotide repeat-containing gene 6C protein (TNRC6C).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Trinucleotide repeat-containing gene 6C protein (TNRC6C).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Trinucleotide repeat-containing gene 6C protein (TNRC6C).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Trinucleotide repeat-containing gene 6C protein (TNRC6C).	[11]

References

• [1] DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure.Clin Epigenetics. 2019 Oct 15;11(1):142. doi: 10.1186/s13148-019-0705-2.
• [2] Oncogene GAEC1 regulates CAPN10 expression which predicts survival in esophageal squamous cell carcinoma.World J Gastroenterol. 2013 May 14;19(18):2772-80. doi: 10.3748/wjg.v19.i18.2772.
• [3] 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.
• [4] Long Non-coding Antisense RNA TNRC6C-AS1 Is Activated in Papillary Thyroid Cancer and Promotes Cancer Progression by Suppressing TNRC6C Expression.Front Endocrinol (Lausanne). 2018 Jul 9;9:360. doi: 10.3389/fendo.2018.00360. eCollection 2018.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] 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.
• [12] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.