Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAXU2QD)

• DOT Name: Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A)
• Synonyms: NS4EA; Non-SMC element 4 homolog A
• Gene Name: NSMCE4A
• UniProt ID: NSE4A_HUMAN
• Pfam ID: PF15412 ; PF08743
• Sequence:
  MSGDSSGRGPEGRGRGRDPHRDRTRSRSRSRSPLSPRSRRGSARERREAPERPSLEDTEP
  SDSGDEMMDPASLEAEADQGLCRQIRHQYRALINSVQQNREDILNAGDKLTEVLEEANTL
  FNEVSRAREAVLDAHFLVLASDLGKEKAKQLRSDLSSFDMLRYVETLLTHMGVNPLEAEE
  LIRDEDSPDFEFIVYDSWKITGRTAENTFNKTHTFHFLLGSIYGECPVPKPRVDRPRKVP
  VIQEERAMPAQLRRMEESHQEATEKEVERILGLLQTYFREDPDTPMSFFDFVVDPHSFPR
  TVENIFHVSFIIRDGFARIRLDQDRLPVIEPVSINEENEGFEHNTQVRNQGIIALSYRDW
  EEIVKTFEISEPVITPSQRQQKPSA
• Function: Component of the SMC5-SMC6 complex, a complex involved in 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). Is involved in positive regulation of response to DNA damage stimulus.
• Reactome Pathway: SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)

Molecular Interaction Atlas (MIA) of This DOT

13 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 Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[12]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the methylation of Non-structural maintenance of chromosomes element 4 homolog A (NSMCE4A).	[16]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [16] Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women. Environ Health Perspect. 2022 Apr;130(4):47001. doi: 10.1289/EHP10174. Epub 2022 Apr 4.