Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZCNM33)

• DOT Name: RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2)
• Synonyms: EC 2.1.1.-; Myc-induced SUN domain-containing protein; Misu; NOL1/NOP2/Sun domain family member 2; Substrate of AIM1/Aurora kinase B; mRNA cytosine C(5)-methyltransferase; EC 2.1.1.-; tRNA cytosine C(5)-methyltransferase; EC 2.1.1.-, EC 2.1.1.203; tRNA methyltransferase 4 homolog; hTrm4
• Gene Name: NSUN2
• Related Disease:
  Autosomal recessive hypophosphatemic rickets
  Colorectal carcinoma
  Disorder of glycogen metabolism
  Hurler syndrome
  Autism spectrum disorder
  Breast cancer
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Hepatitis C virus infection
  Hereditary hemochromatosis
  Intellectual disability, autosomal recessive 5
  Neoplasm
  Neurodevelopmental disorder
  Ovarian cancer
  Ovarian neoplasm
  Head-neck squamous cell carcinoma
  Intellectual disability
  Autosomal recessive non-syndromic intellectual disability
  Dubowitz syndrome
  Gallbladder cancer
  Gallbladder carcinoma
  RASopathy
  Advanced cancer
  Breast carcinoma
  Isolated congenital microcephaly
  Squamous cell carcinoma
• UniProt ID: NSUN2_HUMAN
• EC Number: 2.1.1.-; 2.1.1.203
• Pfam ID: PF01189
• Sequence:
  MGRRSRGRRLQQQQRPEDAEDGAEGGGKRGEAGWEGGYPEIVKENKLFEHYYQELKIVPE
  GEWGQFMDALREPLPATLRITGYKSHAKEILHCLKNKYFKELEDLEVDGQKVEVPQPLSW
  YPEELAWHTNLSRKILRKSPHLEKFHQFLVSETESGNISRQEAVSMIPPLLLNVRPHHKI
  LDMCAAPGSKTTQLIEMLHADMNVPFPEGFVIANDVDNKRCYLLVHQAKRLSSPCIMVVN
  HDASSIPRLQIDVDGRKEILFYDRILCDVPCSGDGTMRKNIDVWKKWTTLNSLQLHGLQL
  RIATRGAEQLAEGGRMVYSTCSLNPIEDEAVIASLLEKSEGALELADVSNELPGLKWMPG
  ITQWKVMTKDGQWFTDWDAVPHSRHTQIRPTMFPPKDPEKLQAMHLERCLRILPHHQNTG
  GFFVAVLVKKSSMPWNKRQPKLQGKSAETRESTQLSPADLTEGKPTDPSKLESPSFTGTG
  DTEIAHATEDLENNGSKKDGVCGPPPSKKMKLFGFKEDPFVFIPEDDPLFPPIEKFYALD
  PSFPRMNLLTRTTEGKKRQLYMVSKELRNVLLNNSEKMKVINTGIKVWCRNNSGEEFDCA
  FRLAQEGIYTLYPFINSRIITVSMEDVKILLTQENPFFRKLSSETYSQAKDLAKGSIVLK
  YEPDSANPDALQCPIVLCGWRGKASIRTFVPKNERLHYLRMMGLEVLGEKKKEGVILTNE
  SAASTGQPDNDVTEGQRAGEPNSPDAEEANSPDVTAGCDPAGVHPPR
• Function: RNA cytosine C(5)-methyltransferase that methylates cytosine to 5-methylcytosine (m5C) in various RNAs, such as tRNAs, mRNAs and some long non-coding RNAs (lncRNAs). Involved in various processes, such as epidermal stem cell differentiation, testis differentiation and maternal to zygotic transition during early development: acts by increasing protein synthesis; cytosine C(5)-methylation promoting tRNA stability and preventing mRNA decay. Methylates cytosine to 5-methylcytosine (m5C) at positions 34 and 48 of intron-containing tRNA(Leu)(CAA) precursors, and at positions 48, 49 and 50 of tRNA(Gly)(GCC) precursors. tRNA methylation is required generation of RNA fragments derived from tRNAs (tRFs). Also mediates C(5)-methylation of mitochondrial tRNAs. Catalyzes cytosine C(5)-methylation of mRNAs, leading to stabilize them and prevent mRNA decay: mRNA stabilization involves YBX1 that specifically recognizes and binds m5C-modified transcripts. Cytosine C(5)-methylation of mRNAs also regulates mRNA export: methylated transcripts are specifically recognized by THOC4/ALYREF, which mediates mRNA nucleo-cytoplasmic shuttling. Also mediates cytosine C(5)-methylation of non-coding RNAs, such as vault RNAs (vtRNAs), promoting their processing into regulatory small RNAs. Cytosine C(5)-methylation of vtRNA VTRNA1.1 promotes its processing into small-vault RNA4 (svRNA4) and regulates epidermal differentiation. May act downstream of Myc to regulate epidermal cell growth and proliferation. Required for proper spindle assembly and chromosome segregation, independently of its methyltransferase activity.
• Tissue Specificity: Expressed in adult and fetal brain and in lymphoblastoid cells.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)
• BioCyc Pathway: MetaCyc:HS12087-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive hypophosphatemic rickets	DIS8E3KA	Definitive	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[2]
Disorder of glycogen metabolism	DISYGNOB	Definitive	Genetic Variation	[1]
Hurler syndrome	DIS1DPSN	Definitive	Genetic Variation	[1]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Hereditary hemochromatosis	DISVG5MT	Strong	Biomarker	[7]
Intellectual disability, autosomal recessive 5	DISCHMH1	Strong	Autosomal recessive	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Genetic Variation	[11]
Intellectual disability	DISMBNXP	moderate	Biomarker	[12]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[13]
Dubowitz syndrome	DISRMNLQ	Supportive	Autosomal recessive	[8]
Gallbladder cancer	DISXJUAF	Disputed	Altered Expression	[14]
Gallbladder carcinoma	DISD6ACL	Disputed	Altered Expression	[14]
RASopathy	DISPAV44	Disputed	Autosomal recessive	[15]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[4]
Isolated congenital microcephaly	DISUXHZ6	Limited	Genetic Variation	[16]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[25]
Menadione	DMSJDTY	Approved	Menadione affects the expression of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[29]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[24]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of RNA cytosine C(5)-methyltransferase NSUN2 (NSUN2).	[28]

References

• [1] Whole exome sequencing unravels disease-causing genes in consanguineous families in Qatar. Clin Genet. 2014 Aug;86(2):134-41. doi: 10.1111/cge.12280. Epub 2013 Oct 13.
• [2] Frequent increased gene copy number and high protein expression of tRNA (cytosine-5-)-methyltransferase (NSUN2) in human cancers.DNA Cell Biol. 2012 May;31(5):660-71. doi: 10.1089/dna.2011.1446. Epub 2011 Dec 2.
• [3] Recessive gene disruptions in autism spectrum disorder.Nat Genet. 2019 Jul;51(7):1092-1098. doi: 10.1038/s41588-019-0433-8. Epub 2019 Jun 17.
• [4] Overexpression of NSUN2 by DNA hypomethylation is associated with metastatic progression in human breast cancer.Oncotarget. 2017 Mar 28;8(13):20751-20765. doi: 10.18632/oncotarget.10612.
• [5] Association of tRNA methyltransferase NSUN2/IGF-II molecular signature with ovarian cancer survival.Future Oncol. 2017 Sep;13(22):1981-1990. doi: 10.2217/fon-2017-0084. Epub 2017 Aug 22.
• [6] Novel long noncoding RNA NMR promotes tumor progression via NSUN2 and BPTF in esophageal squamous cell carcinoma.Cancer Lett. 2018 Aug 28;430:57-66. doi: 10.1016/j.canlet.2018.05.013. Epub 2018 May 12.
• [7] In vitro-targeted gene identification in patients with hepatitis C using a genome-wide microarray technology.Hepatology. 2009 Feb;49(2):378-86. doi: 10.1002/hep.22677.
• [8] Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. J Med Genet. 2012 Jun;49(6):380-5. doi: 10.1136/jmedgenet-2011-100686. Epub 2012 May 10.
• [9] Expression profiles of long noncoding RNAs associated with the NSUN2 gene in HepG2 cells.Mol Med Rep. 2019 Apr;19(4):2999-3008. doi: 10.3892/mmr.2019.9984. Epub 2019 Feb 25.
• [10] NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs.Nucleic Acids Res. 2019 Sep 19;47(16):8720-8733. doi: 10.1093/nar/gkz559.
• [11] DNA methylation-mediated Klotho silencing is an independent prognostic biomarker of head and neck squamous carcinoma.Cancer Manag Res. 2019 Feb 12;11:1383-1390. doi: 10.2147/CMAR.S188415. eCollection 2019.
• [12] Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol Psychiatry. 2018 Apr;23(4):973-984. doi: 10.1038/mp.2017.60. Epub 2017 Apr 11.
• [13] Mutations in NSUN2 cause autosomal-recessive intellectual disability. Am J Hum Genet. 2012 May 4;90(5):847-55. doi: 10.1016/j.ajhg.2012.03.021. Epub 2012 Apr 26.
• [14] NOP2/Sun RNA methyltransferase 2 promotes tumor progression via its interacting partner RPL6 in gallbladder carcinoma.Cancer Sci. 2019 Nov;110(11):3510-3519. doi: 10.1111/cas.14190. Epub 2019 Sep 23.
• [15] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [16] Cytosine-5 RNA Methylation Regulates Neural Stem Cell Differentiation andMotility.Stem Cell Reports. 2017 Jan 10;8(1):112-124. doi: 10.1016/j.stemcr.2016.11.014. Epub 2016 Dec 29.
• [17] High tRNA Transferase NSUN2 Gene Expression is Associated with Poor Prognosis in Head and Neck Squamous Carcinoma.Cancer Invest. 2018 Apr 21;36(4):246-253. doi: 10.1080/07357907.2018.1466896.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] 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.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] 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.
• [23] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [24] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.