Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPBRUH6)

• DOT Name: tRNA (NSUN6)
• Synonyms: cytosine(72)-C(5))-methyltransferase NSUN6 (EC 2.1.1.-; NOL1/NOP2/Sun and PUA domain-containing protein 1; NOL1/NOP2/Sun domain family member 6
• Gene Name: NSUN6
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Schizophrenia
• UniProt ID: NSUN6_HUMAN
• PDB ID: 5WWQ; 5WWR; 5WWS; 5WWT
• EC Number: 2.1.1.-
• Pfam ID: PF01189
• Sequence:
  MSIFPKISLRPEVENYLKEGFMNKEIVTALGKQEAERKFETLLKHLSHPPSFTTVRVNTH
  LASVQHVKNLLLDELQKQFNGLSVPILQHPDLQDVLLIPVIGPRKNIKKQQCEAIVGAQC
  GNAVLRGAHVYAPGIVSASQFMKAGDVISVYSDIKGKCKKGAKEFDGTKVFLGNGISELS
  RKEIFSGLPELKGMGIRMTEPVYLSPSFDSVLPRYLFLQNLPSALVSHVLNPQPGEKILD
  LCAAPGGKTTHIAALMHDQGEVIALDKIFNKVEKIKQNALLLGLNSIRAFCFDGTKAVKL
  DMVEDTEGEPPFLPESFDRILLDAPCSGMGQRPNMACTWSVKEVASYQPLQRKLFTAAVQ
  LLKPEGVLVYSTCTITLAENEEQVAWALTKFPCLQLQPQEPQIGGEGMRGAGLSCEQLKQ
  LQRFDPSAVPLPDTDMDSLREARREDMLRLANKDSIGFFIAKFVKCKST
• Function: S-adenosyl-L-methionine-dependent methyltransferase that specifically methylates the C5 position of cytosine 72 in tRNA(Thr)(TGT) and tRNA(Cys)(GCA). In vitro also methylates tRNA(Thr)(AGT). Methylation requires, in the acceptor stem region, the presence of the 3'-CCA terminus, the target site C72, the discriminator base U73, and the second and third base pairs (2:71 and 3:70) in the tRNA substrates.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[2]

11 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 tRNA (NSUN6).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of tRNA (NSUN6).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of tRNA (NSUN6).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of tRNA (NSUN6).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA (NSUN6).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of tRNA (NSUN6).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of tRNA (NSUN6).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA (NSUN6).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of tRNA (NSUN6).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of tRNA (NSUN6).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of tRNA (NSUN6).	[13]

References

• [1] A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis.Nat Cell Biol. 2017 Feb;19(2):106-119. doi: 10.1038/ncb3464. Epub 2017 Jan 23.
• [2] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [3] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.