Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUF6FWW)

• DOT Name: Terminal nucleotidyltransferase 4B (TENT4B)
• Synonyms: Non-canonical poly(A) RNA polymerase PAPD5; EC 2.7.7.19; PAP-associated domain-containing protein 5; Terminal guanylyltransferase; EC 2.7.7.-; Terminal uridylyltransferase 3; TUTase 3; Topoisomerase-related function protein 4-2; TRF4-2
• Gene Name: TENT4B
• UniProt ID: PAPD5_HUMAN
• EC Number: 2.7.7.-; 2.7.7.19
• Pfam ID: PF01909 ; PF03828
• Sequence:
  MYRSGERLLGSHALPAEQRDFLPLETTNNNNNHHQPGAWARRAGSSASSPPSASSSPHPS
  AAVPAADPADSASGSSNKRKRDNKASGGRAAGGGRADGGGVVYSGTPWKRRNYNQGVVGL
  HEEISDFYEYMSPRPEEEKMRMEVVNRIESVIKELWPSADVQIFGSFKTGLYLPTSDIDL
  VVFGKWENLPLWTLEEALRKHKVADEDSVKVLDKATVPIIKLTDSFTEVKVDISFNVQNG
  VRAADLIKDFTKKYPVLPYLVLVLKQFLLQRDLNEVFTGGIGSYSLFLMAVSFLQLHPRE
  DACIPNTNYGVLLIEFFELYGRHFNYLKTGIRIKDGGSYVAKDEVQKNMLDGYRPSMLYI
  EDPLQPGNDVGRSSYGAMQVKQAFDYAYVVLSHAVSPIAKYYPNNETESILGRIIRVTDE
  VATYRDWISKQWGLKNRPEPSCNGPVSSSSATQSSSSDVDSDATPCKTPKQLLCRPSTGN
  RVGSQDVSLESSQAVGKMQSTQTTNTSNSTNKSQHGSARLFRSSSKGFQGTTQTSHGSLM
  TNKQHQGKSNNQYYHGKKRKHKRDAPLSDLCR
• 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. Doesn't need a cofactor for polyadenylation activity (in vitro). Required for cytoplasmic polyadenylation of mRNAs involved in carbohydrate metabolism, including the glucose transporter SLC2A1/GLUT1. Plays a role in replication-dependent histone mRNA degradation, probably through terminal uridylation of mature histone mRNAs. May play a role in sister chromatid cohesion. Mediates 3' adenylation of the microRNA MIR21 followed by its 3'-to-5' trimming by the exoribonuclease PARN leading to degradation. Mediates 3' adenylation of H/ACA box snoRNAs (small nucleolar RNAs) followed by its 3'-to-5' trimming by the exoribonuclease PARN which enhances snoRNA stability and maturation.
• KEGG Pathway: R. degradation (hsa03018)

Molecular Interaction Atlas (MIA) of This DOT

3 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 Terminal nucleotidyltransferase 4B (TENT4B).	[1]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Terminal nucleotidyltransferase 4B (TENT4B).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Terminal nucleotidyltransferase 4B (TENT4B).	[8]

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 4B (TENT4B).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Terminal nucleotidyltransferase 4B (TENT4B).	[3]
2-deoxyglucose	DMIAHVU	Approved	2-deoxyglucose decreases the expression of Terminal nucleotidyltransferase 4B (TENT4B).	[4]
Bleomycin	DMNER5S	Approved	Bleomycin decreases the expression of Terminal nucleotidyltransferase 4B (TENT4B).	[4]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Terminal nucleotidyltransferase 4B (TENT4B).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Terminal nucleotidyltransferase 4B (TENT4B).	[6]
Scriptaid	DM9JZ21	Preclinical	Scriptaid increases the expression of Terminal nucleotidyltransferase 4B (TENT4B).	[4]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Terminal nucleotidyltransferase 4B (TENT4B).	[9]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Terminal nucleotidyltransferase 4B (TENT4B).	[10]

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] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [7] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [8] 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.
• [9] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [10] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.