Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJS7VU3)

• DOT Name: Probable 18S rRNA (BUD23)
• Synonyms: guanine-N(7))-methyltransferase (EC 2.1.1.-; Bud site selection protein 23 homolog; Metastasis-related methyltransferase 1; Williams-Beuren syndrome chromosomal region 22 protein; rRNA methyltransferase and ribosome maturation factor
• Gene Name: BUD23
• Related Disease:
  Advanced cancer
  Pneumonia
  Pneumonitis
  Pulmonary disease
  Colorectal carcinoma
  Metastatic malignant neoplasm
• UniProt ID: BUD23_HUMAN
• PDB ID: 6G4W; 7WTS; 7WTT; 7WTU; 7WTV; 7WTW
• EC Number: 2.1.1.-
• Pfam ID: PF08241 ; PF12589
• Sequence:
  MASRGRRPEHGGPPELFYDETEARKYVRNSRMIDIQTRMAGRALELLYLPENKPCYLLDI
  GCGTGLSGSYLSDEGHYWVGLDISPAMLDEAVDREIEGDLLLGDMGQGIPFKPGTFDGCI
  SISAVQWLCNANKKSENPAKRLYCFFASLFSVLVRGSRAVLQLYPENSEQLELITTQATK
  AGFSGGMVVDYPNSAKAKKFYLCLFSGPSTFIPEGLSENQDEVEPRESVFTNERFPLRMS
  RRGMVRKSRAWVLEKKERHRRQGREVRPDTQYTGRKRKPRF
• Function: S-adenosyl-L-methionine-dependent methyltransferase that specifically methylates the N(7) position of a guanine in 18S rRNA. Requires the methyltransferase adapter protein TRM112 for full rRNA methyltransferase activity. Involved in the pre-rRNA processing steps leading to small-subunit rRNA production independently of its RNA-modifying catalytic activity. Important for biogenesis end export of the 40S ribosomal subunit independent on its methyltransferase activity. Locus-specific steroid receptor coactivator. Potentiates transactivation by glucocorticoid (NR3C1), mineralocorticoid (NR3C2), androgen (AR) and progesterone (PGR) receptors. Required for the maintenance of open chromatin at the TSC22D3/GILZ locus to facilitate NR3C1 loading on the response elements. Required for maintenance of dimethylation on histone H3 'Lys-79' (H3K79me2), although direct histone methyltransferase activity is not observed in vitro.
• Tissue Specificity: Widely expressed, with high levels in heart, skeletal muscle and kidney. Detected at high levels in bronchial brushings and in normal lung (at protein level). In fetal lung tissue, expressed in the developing bronchial lumen lining cells (at protein level). Tends to be down-regulated in lungs affected by inflammatory diseases or neoplasia (at protein level). Expressed in immune cells, including B and T lymphocytes and macrophages.
• Reactome Pathway:
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Pneumonia	DIS8EF3M	Strong	Biomarker	[1]
Pneumonitis	DIS88E0K	Strong	Biomarker	[1]
Pulmonary disease	DIS6060I	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[2]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[3]

8 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 Probable 18S rRNA (BUD23).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Probable 18S rRNA (BUD23).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Probable 18S rRNA (BUD23).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Probable 18S rRNA (BUD23).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Probable 18S rRNA (BUD23).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Probable 18S rRNA (BUD23).	[9]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Probable 18S rRNA (BUD23).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Probable 18S rRNA (BUD23).	[11]

References

• [1] The methyltransferase WBSCR22/Merm1 enhances glucocorticoid receptor function and is regulated in lung inflammation and cancer.J Biol Chem. 2014 Mar 28;289(13):8931-46. doi: 10.1074/jbc.M113.540906. Epub 2014 Jan 31.
• [2] Natural killer cells inhibit oxaliplatin-resistant colorectal cancer by repressing WBSCR22 via upregulating microRNA-146b-5p.Am J Cancer Res. 2018 May 1;8(5):824-834. eCollection 2018.
• [3] WBSCR22 confers oxaliplatin resistance in human colorectal cancer.Sci Rep. 2017 Nov 13;7(1):15443. doi: 10.1038/s41598-017-15749-z.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes. Oncogene. 2008 Jan 10;27(3):378-86. doi: 10.1038/sj.onc.1210648. Epub 2007 Jul 9.
• [10] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [11] 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.