Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBD4MSP)

• DOT Name: Non-structural maintenance of chromosomes element 3 homolog (NSMCE3)
• Synonyms: Non-SMC element 3 homolog; Hepatocellular carcinoma-associated protein 4; MAGE-G1 antigen; Melanoma-associated antigen G1; Necdin-like protein 2
• Gene Name: NSMCE3
• Related Disease:
  Adult respiratory distress syndrome
  Neoplasm
  Prader-Willi syndrome
  Retinitis pigmentosa
  Glaucoma/ocular hypertension
• UniProt ID: NSE3_HUMAN
• PDB ID: 5HVQ; 5WY5
• Pfam ID: PF01454
• Sequence:
  MLQKPRNRGRSGGQAERDRDWSHSGNPGASRAGEDARVLRDGFAEEAPSTSRGPGGSQGS
  QGPSPQGARRAQAAPAVGPRSQKQLELKVSELVQFLLIKDQKKIPIKRADILKHVIGDYK
  DIFPDLFKRAAERLQYVFGYKLVELEPKSNTYILINTLEPVEEDAEMRGDQGTPTTGLLM
  IVLGLIFMKGNTIKETEAWDFLRRLGVYPTKKHLIFGDPKKLITEDFVRQRYLEYRRIPH
  TDPVDYEFQWGPRTNLETSKMKVLKFVAKVHNQDPKDWPAQYCEALADEENRARPQPSGP
  APSS
• Function: Component of the SMC5-SMC6 complex, a complex involved in repair of DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). In vitro enhances ubiquitin ligase activity of NSMCE1. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. May be a growth suppressor that facilitates the entry of the cell into cell cycle arrest.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult respiratory distress syndrome	DISIJV47	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Prader-Willi syndrome	DISYWMLU	Strong	Biomarker	[3]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[4]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Non-structural maintenance of chromosomes element 3 homolog (NSMCE3).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Non-structural maintenance of chromosomes element 3 homolog (NSMCE3).	[9]

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 Non-structural maintenance of chromosomes element 3 homolog (NSMCE3).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Non-structural maintenance of chromosomes element 3 homolog (NSMCE3).	[8]

References

• [1] Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease.J Clin Invest. 2016 Aug 1;126(8):2881-92. doi: 10.1172/JCI82890. Epub 2016 Jul 18.
• [2] Synthesis of a new series of 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides as carbonic anhydrase I, II, IV and IX inhibitors.J Enzyme Inhib Med Chem. 2019 Dec;34(1):1199-1209. doi: 10.1080/14756366.2019.1629432.
• [3] A necdin/MAGE-like gene in the chromosome 15 autism susceptibility region: expression, imprinting, and mapping of the human and mouse orthologues.BMC Genet. 2001;2:22. doi: 10.1186/1471-2156-2-22. Epub 2001 Dec 20.
• [4] Continued exploration and tail approach synthesis of benzenesulfonamides containing triazole and dual triazole moieties as carbonic anhydrase I, II, IV and IX inhibitors.Eur J Med Chem. 2019 Dec 1;183:111698. doi: 10.1016/j.ejmech.2019.111698. Epub 2019 Sep 12.
• [5] Design and synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as potent human carbonic anhydrase isoforms I, II, IV and IX inhibitors.Eur J Med Chem. 2018 Jul 15;155:545-551. doi: 10.1016/j.ejmech.2018.06.021. Epub 2018 Jun 8.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] 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.
• [9] 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.