Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY6O37Z)

• DOT Name: 5-methylcytosine rRNA methyltransferase NSUN4 (NSUN4)
• Synonyms: EC 2.1.1.-; 5-methylcytosine tRNA methyltransferase NSUN4; EC 2.1.1.-; NOL1/NOP2/Sun domain family member 4
• Gene Name: NSUN4
• Related Disease:
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
• UniProt ID: NSUN4_HUMAN
• PDB ID: 4FP9; 4FZV; 7O9K; 7O9M; 7ODR; 7ODS; 7ODT; 7OF0; 7OF3; 7OF5; 7OF7; 7OIC; 7PD3
• EC Number: 2.1.1.-
• Pfam ID: PF01189
• Sequence:
  MAALTLRGVRELLKRVDLATVPRRHRYKKKWAATEPKFPAVRLALQNFDMTYSVQFGDLW
  PSIRVSLLSEQKYGALVNNFAAWDHVSAKLEQLSAKDFVNEAISHWELQSEGGQSAAPSP
  ASWACSPNLRCFTFDRGDISRFPPARPGSLGVMEYYLMDAASLLPVLALGLQPGDIVLDL
  CAAPGGKTLALLQTGCCRNLAANDLSPSRIARLQKILHSYVPEEIRDGNQVRVTSWDGRK
  WGELEGDTYDRVLVDVPCTTDRHSLHEEENNIFKRSRKKERQILPVLQVQLLAAGLLATK
  PGGHVVYSTCSLSHLQNEYVVQGAIELLANQYSIQVQVEDLTHFRRVFMDTFCFFSSCQV
  GELVIPNLMANFGPMYFCKMRRLT
• Function: Involved in mitochondrial ribosome assembly. 5-methylcytosine rRNA methyltransferase that probably is involved in mitochondrial ribosome small subunit (SSU) maturation by methylation of mitochondrial 12S rRNA; the function is independent of MTERFD2/MTERF4 and assembled mitochondrial ribosome large subunit (LSU). Targeted to LSU by MTERFD2/MTERF4 and probably is involved in a final step in ribosome biogenesis to ensure that SSU and LSU are assembled. In vitro can methylate 16S rRNA of the LSU; the methylation is enhanced by MTERFD/MTERF4.
• Reactome Pathway: rRNA modification in the mitochondrion (R-HSA-6793080)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[1]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[1]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[1]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[1]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[1]

4 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 5-methylcytosine rRNA methyltransferase NSUN4 (NSUN4).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 5-methylcytosine rRNA methyltransferase NSUN4 (NSUN4).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 5-methylcytosine rRNA methyltransferase NSUN4 (NSUN4).	[4]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of 5-methylcytosine rRNA methyltransferase NSUN4 (NSUN4).	[7]

2 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 5-methylcytosine rRNA methyltransferase NSUN4 (NSUN4).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of 5-methylcytosine rRNA methyltransferase NSUN4 (NSUN4).	[6]

References

• [1] Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.Cancer Discov. 2016 Sep;6(9):1052-67. doi: 10.1158/2159-8290.CD-15-1227. Epub 2016 Jul 17.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.