Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0G3KR0)

• DOT Name: Terminal nucleotidyltransferase 4A (TENT4A)
• Synonyms: DNA polymerase sigma; LAK-1; Non-canonical poly(A) RNA polymerase PAPD7; EC 2.7.7.19; PAP-associated domain-containing protein 7; TRAMP-like complex polyadenylate polymerase; Terminal guanylyltransferase; EC 2.7.7.-; Terminal uridylyltransferase 5; TUTase 5; Topoisomerase-related function protein 4-1; TRF4-1
• Gene Name: TENT4A
• UniProt ID: PAPD7_HUMAN
• EC Number: 2.7.7.-; 2.7.7.19
• Pfam ID: PF01909 ; PF03828
• Sequence:
  MDPRVAWIQPEQKGPANALWMQIWETSQGVGRGGSGFASYFCLNSPALDTAAAAGAAGRG
  SGGLGPALPAASPPPPGPTAPAALPPALLTALGPAAEGARRLHKSPSLSSSSSSSSSNAE
  SGTESPGCSSSSSSSASLGRPGGGRGGAFFNFADGAPSAPGTANGHPGPRGPAPAGSPSQ
  HQFHPGRRKRENKASTYGLNYLLSGSRAAALSGGGGPGAQAPRPGTPWKSRAYSPGIQGL
  HEEIIDFYNFMSPCPEEAAMRREVVKRIETVVKDLWPTADVQIFGSFSTGLYLPTSDIDL
  VVFGKWERPPLQLLEQALRKHNVAEPCSIKVLDKATVPIIKLTDQETEVKVDISFNMETG
  VRAAEFIKNYMKKYSLLPYLILVLKQFLLQRDLNEVFTGGISSYSLILMAISFLQLHPRI
  DARRADENLGMLLVEFFELYGRNFNYLKTGIRIKEGGAYIAKEEIMKAMTSGYRPSMLCI
  EDPLLPGNDVGRSSYGAMQVKQVFDYAYIVLSHAVSPLARSYPNRDAESTLGRIIKVTQE
  VIDYRRWIKEKWGSKAHPSPGMDSRIKIKERIATCNGEQTQNREPESPYGQRLTLSLSSP
  QLLSSGSSASSVSSLSGSDVDSDTPPCTTPSVYQFSLQAPAPLMAGLPTALPMPSGKPQP
  TTSRTLIMTTNNQTRFTIPPPTLGVAPVPCRQAGVEGTASLKAVHHMSSPAIPSASPNPL
  SSPHLYHKQHNGMKLSMKGSHGHTQGGGYSSVGSGGVRPPVGNRGHHQYNRTGWRRKKHT
  HTRDSLPVSLSR
• Function: Terminal nucleotidyltransferase that catalyzes preferentially the transfer of ATP and GTP on RNA 3' poly(A) tail creating a heterogeneous 3' poly(A) tail leading to mRNAs stabilization by protecting mRNAs from active deadenylation. Also functions as a catalytic subunit of a TRAMP-like complex which has a poly(A) RNA polymerase activity and is involved in a post-transcriptional quality control mechanism. Polyadenylation with short oligo(A) tails is required for the degradative activity of the exosome on several of its nuclear RNA substrates. Has no terminal uridylyltransferase activity, and does not play a role in replication-dependent histone mRNA degradation via uridylation.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway: Signaling by BRAF and RAF1 fusions (R-HSA-6802952)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Brilinta	DMBR01X	Approved	Terminal nucleotidyltransferase 4A (TENT4A) increases the Peripheral sensory neuropathy ADR of Brilinta.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Terminal nucleotidyltransferase 4A (TENT4A).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Terminal nucleotidyltransferase 4A (TENT4A).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Terminal nucleotidyltransferase 4A (TENT4A).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Terminal nucleotidyltransferase 4A (TENT4A).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Terminal nucleotidyltransferase 4A (TENT4A).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Terminal nucleotidyltransferase 4A (TENT4A).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Terminal nucleotidyltransferase 4A (TENT4A).	[5]
Nicotine	DMWX5CO	Approved	Nicotine increases the splicing of Terminal nucleotidyltransferase 4A (TENT4A).	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Terminal nucleotidyltransferase 4A (TENT4A).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Terminal nucleotidyltransferase 4A (TENT4A).	[9]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Terminal nucleotidyltransferase 4A (TENT4A).	[11]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Terminal nucleotidyltransferase 4A (TENT4A).	[12]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.
• [13] Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy. J Med Genet. 2013 Sep;50(9):599-605. doi: 10.1136/jmedgenet-2012-101466. Epub 2013 Jun 17.