Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4DEXG6)

• DOT Name: tRNA (TRMT6)
• Synonyms: adenine(58)-N(1))-methyltransferase non-catalytic subunit TRM6 (mRNA methyladenosine-N(1)-methyltransferase non-catalytic subunit TRM6; tRNA(m1A58)-methyltransferase subunit TRM6; tRNA(m1A58)MTase subunit TRM6
• Gene Name: TRMT6
• Related Disease:
  Hepatocellular carcinoma
  Glioblastoma multiforme
• UniProt ID: TRM6_HUMAN
• PDB ID: 5CCB; 5CCX; 5CD1
• Pfam ID: PF04189
• Sequence:
  MEGSGEQPGPQPQHPGDHRIRDGDFVVLKREDVFKAVQVQRRKKVTFEKQWFYLDNVIGH
  SYGTAFEVTSGGSLQPKKKREEPTAETKEAGTDNRNIVDDGKSQKLTQDDIKALKDKGIK
  GEEIVQQLIENSTTFRDKTEFAQDKYIKKKKKKYEAIITVVKPSTRILSIMYYAREPGKI
  NHMRYDTLAQMLTLGNIRAGNKMIVMETCAGLVLGAMMERMGGFGSIIQLYPGGGPVRAA
  TACFGFPKSFLSGLYEFPLNKVDSLLHGTFSAKMLSSEPKDSALVEESNGTLEEKQASEQ
  ENEDSMAEAPESNHPEDQETMETISQDPEHKGPKERGSKKDYIQEKQRRQEEQRKRHLEA
  AALLSERNADGLIVASRFHPTPLLLSLLDFVAPSRPFVVYCQYKEPLLECYTKLRERGGV
  INLRLSETWLRNYQVLPDRSHPKLLMSGGGGYLLSGFTVAMDNLKADTSLKSNASTLESH
  ETEEPAAKKRKCPESDS
• Function: Substrate-binding subunit of tRNA (adenine-N(1)-)-methyltransferase, which catalyzes the formation of N(1)-methyladenine at position 58 (m1A58) in initiator methionyl-tRNA. Together with the TRMT61A catalytic subunit, part of a mRNA N(1)-methyltransferase complex that mediates methylation of adenosine residues at the N(1) position of a small subset of mRNAs: N(1) methylation takes place in tRNA T-loop-like structures of mRNAs and is only present at low stoichiometries.
• Tissue Specificity: Expressed in brain, liver, testis and ovary.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[2]

1 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 tRNA (TRMT6).	[3]

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 tRNA (TRMT6).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of tRNA (TRMT6).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of tRNA (TRMT6).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of tRNA (TRMT6).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA (TRMT6).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of tRNA (TRMT6).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of tRNA (TRMT6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of tRNA (TRMT6).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of tRNA (TRMT6).	[13]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of tRNA (TRMT6).	[9]

References

• [1] Clinical Significance of TRMT6 in Hepatocellular Carcinoma: A Bioinformatics-Based Study.Med Sci Monit. 2019 May 25;25:3894-3901. doi: 10.12659/MSM.913556.
• [2] TRM6/61 connects PKC with translational control through tRNAi(Met) stabilization: impact on tumorigenesis.Oncogene. 2016 Apr 7;35(14):1785-96. doi: 10.1038/onc.2015.244. Epub 2015 Aug 3.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [10] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [11] 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.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.