Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZJTA5X)

• DOT Name: Non-structural maintenance of chromosomes element 1 homolog (NSMCE1)
• Synonyms: Non-SMC element 1 homolog; EC 2.3.2.27
• Gene Name: NSMCE1
• Related Disease:
  Advanced cancer
  Peripheral arterial disease
  Prostate cancer
  Prostate carcinoma
• UniProt ID: NSE1_HUMAN
• PDB ID: 2CT0; 5HVQ; 5WY5
• EC Number: 2.3.2.27
• Pfam ID: PF07574 ; PF08746
• Sequence:
  MQGSTRRMGVMTDVHRRFLQLLMTHGVLEEWDVKRLQTHCYKVHDRNATVDKLEDFINNI
  NSVLESLYIEIKRGVTEDDGRPIYALVNLATTSISKMATDFAENELDLFRKALELIIDSE
  TGFASSTNILNLVDQLKGKKMRKKEAEQVLQKFVQNKWLIEKEGEFTLHGRAILEMEQYI
  RETYPDAVKICNICHSLLIQGQSCETCGIRMHLPCVAKYFQSNAEPRCPHCNDYWPHEIP
  KVFDPEKERESGVLKSNKKSLRSRQH
• Function: RING-type zinc finger-containing E3 ubiquitin ligase that assembles with melanoma antigen protein (MAGE) to catalyze the direct transfer of ubiquitin from E2 ubiquitin-conjugating enzyme to a specific substrate. Within MAGE-RING ubiquitin ligase complex, MAGE stimulates and specifies ubiquitin ligase activity likely through recruitment and/or stabilization of the E2 ubiquitin-conjugating enzyme at the E3:substrate complex. Involved in maintenance of genome integrity, DNA damage response and DNA repair. NSMCE3/MAGEG1 and NSMCE1 ubiquitin ligase are components of SMC5-SMC6 complex and may positively regulate homologous recombination-mediated DNA repair. MAGEF1-NSMCE1 ubiquitin ligase promotes proteasomal degradation of MMS19, a key component of the cytosolic iron-sulfur protein assembly (CIA) machinery. Down-regulation of MMS19 impairs the activity of several DNA repair and metabolism enzymes such as ERCC2/XPD, FANCJ, RTEL1 and POLD1 that require iron-sulfur clusters as cofactors.
• Reactome Pathway: SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[1]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Non-structural maintenance of chromosomes element 1 homolog (NSMCE1).	[3]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Non-structural maintenance of chromosomes element 1 homolog (NSMCE1).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Non-structural maintenance of chromosomes element 1 homolog (NSMCE1).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Non-structural maintenance of chromosomes element 1 homolog (NSMCE1).	[8]

2 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 affects the methylation of Non-structural maintenance of chromosomes element 1 homolog (NSMCE1).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Non-structural maintenance of chromosomes element 1 homolog (NSMCE1).	[7]

References

• [1] Identification of novel tumor markers in prostate, colon and breast cancer by unbiased methylation profiling.PLoS One. 2008 Apr 30;3(4):e2079. doi: 10.1371/journal.pone.0002079.
• [2] Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.PLoS One. 2016 Apr 15;11(4):e0152670. doi: 10.1371/journal.pone.0152670. eCollection 2016.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [5] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [6] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [7] 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.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.