Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJXLDC9)

• DOT Name: E3 SUMO-protein ligase NSE2 (NSMCE2)
• Synonyms: EC 2.3.2.-; E3 SUMO-protein transferase NSE2; MMS21 homolog; hMMS21; Non-structural maintenance of chromosomes element 2 homolog; Non-SMC element 2 homolog
• Gene Name: NSMCE2
• Related Disease:
  Acute myelogenous leukaemia
  Breast cancer
  Isolated growth hormone deficiency type IA
  Progressive multifocal leukoencephalopathy
  Schizophrenia
  Seckel syndrome 10
  Breast carcinoma
  Obsolete microcephalic primordial dwarfism-insulin resistance syndrome
  Advanced cancer
• UniProt ID: NSE2_HUMAN
• PDB ID: 2YU4
• EC Number: 2.3.2.-
• Pfam ID: PF11789
• Sequence:
  MPGRSSSNSGSTGFISFSGVESALSSLKNFQACINSGMDTASSVALDLVESQTEVSSEYS
  MDKAMVEFATLDRQLNHYVKAVQSTINHVKEERPEKIPDLKLLVEKKFLALQSKNSDADF
  QNNEKFVQFKQQLKELKKQCGLQADREADGTEGVDEDIIVTQSQTNFTCPITKEEMKKPV
  KNKVCGHTYEEDAIVRMIESRQKRKKKAYCPQIGCSHTDIRKSDLIQDEALRRAIENHNK
  KRHRHSE
• Function: E3 SUMO-protein ligase component of the SMC5-SMC6 complex, a complex involved in DNA double-strand break repair by homologous recombination. Is not be required for the stability of the complex. 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). Acts as an E3 ligase mediating SUMO attachment to various proteins such as SMC6L1 and TSNAX, the shelterin complex subunits TERF1, TERF2, TINF2 and TERF2IP, RAD51AP1, and maybe the cohesin components RAD21 and STAG2. Required for recruitment of telomeres to PML nuclear bodies. SUMO protein-ligase activity is required for the prevention of DNA damage-induced apoptosis by facilitating DNA repair, and for formation of APBs in ALT cell lines. Required for sister chromatid cohesion during prometaphase and mitotic progression.
• Reactome Pathway: SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Isolated growth hormone deficiency type IA	DISLPIAM	Strong	Biomarker	[3]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[5]
Seckel syndrome 10	DISBT6UM	Strong	Autosomal recessive	[6]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[2]
Obsolete microcephalic primordial dwarfism-insulin resistance syndrome	DISQPKO8	Supportive	Autosomal recessive	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 SUMO-protein ligase NSE2 (NSMCE2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 SUMO-protein ligase NSE2 (NSMCE2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 SUMO-protein ligase NSE2 (NSMCE2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of E3 SUMO-protein ligase NSE2 (NSMCE2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 SUMO-protein ligase NSE2 (NSMCE2).	[12]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of E3 SUMO-protein ligase NSE2 (NSMCE2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 SUMO-protein ligase NSE2 (NSMCE2).	[16]

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 E3 SUMO-protein ligase NSE2 (NSMCE2).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 SUMO-protein ligase NSE2 (NSMCE2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of E3 SUMO-protein ligase NSE2 (NSMCE2).	[17]

References

• [1] 8q24 amplified segments involve novel fusion genes between NSMCE2 and long noncoding RNAs in acute myelogenous leukemia.J Hematol Oncol. 2014 Sep 23;7:68. doi: 10.1186/s13045-014-0068-2.
• [2] Depletion of SUMO ligase hMMS21 impairs G1 to S transition in MCF-7 breast cancer cells.Biochim Biophys Acta. 2012 Dec;1820(12):1893-900. doi: 10.1016/j.bbagen.2012.08.002. Epub 2012 Aug 10.
• [3] Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance. J Clin Invest. 2014 Sep;124(9):4028-38. doi: 10.1172/JCI73264. Epub 2014 Aug 8.
• [4] De novo assembly of a PML nuclear subcompartment occurs through multiple pathways and induces telomere elongation.J Cell Sci. 2011 Nov 1;124(Pt 21):3603-18. doi: 10.1242/jcs.084681. Epub 2011 Nov 1.
• [5] Genome-wide association study of paliperidone efficacy.Pharmacogenet Genomics. 2017 Jan;27(1):7-18. doi: 10.1097/FPC.0000000000000250.
• [6] Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer. Genet Med. 2015 Feb;17(2):131-42. doi: 10.1038/gim.2014.89. Epub 2014 Jul 24.
• [7] Trivial role for NSMCE2 during in vitro proliferation and differentiation of male germline stem cells.Reproduction. 2017 Sep;154(3):181-195. doi: 10.1530/REP-17-0173. Epub 2017 Jun 2.
• [8] 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.
• [9] 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.
• [10] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.