Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD9RKD9)

• DOT Name: Crossover junction endonuclease EME1 (EME1)
• Synonyms: EC 3.1.22.-; MMS4 homolog; hMMS4
• Gene Name: EME1
• Related Disease:
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Neoplasm
• UniProt ID: EME1_HUMAN
• PDB ID: 2ZIU; 2ZIV; 2ZIW; 2ZIX; 4P0P; 4P0Q; 4P0R; 4P0S
• EC Number: 3.1.22.-
• Pfam ID: PF21292 ; PF02732
• Sequence:
  MALKKSSPSLDSGDSDSEELPTFAFLKKEPSSTKRRQPEREEKIVVVDISDCEASCPPAP
  ELFSPPVPEIAETVTQTQPVRLLSSESEDEEEFIPLAQRLTCKFLTHKQLSPEDSSSPVK
  SVLDHQNNEGASCDWKKPFPKIPEVPLHDTPERSAADNKDLILDPCCQLPAYLSTCPGQS
  SSLAVTKTNSDILPPQKKTKPSQKVQGRGSHGCRQQRQARQKESTLRRQERKNAALVTRM
  KAQRPEECLKHIIVVLDPVLLQMEGGGQLLGALQTMECRCVIEAQAVPCSVTWRRRAGPS
  EDREDWVEEPTVLVLLRAEAFVSMIDNGKQGSLDSTMKGKETLQGFVTDITAKTAGKALS
  LVIVDQEKCFSAQNPPRRGKQGANKQTKKQQQRQPEASIGSMVSRVDAEEALVDLQLHTE
  AQAQIVQSWKELADFTCAFTKAVAEAPFKKLRDETTFSFCLESDWAGGVKVDLAGRGLAL
  VWRRQIQQLNRVSLEMASAVVNAYPSPQLLVQAYQQCFSDKERQNLLADIQVRRGEGVTS
  TSRRIGPELSRRIYLQMTTLQPHLSLDSAD
• Function: Interacts with MUS81 to form a DNA structure-specific endonuclease with substrate preference for branched DNA structures with a 5'-end at the branch nick. Typical substrates include 3'-flap structures, replication forks and nicked Holliday junctions. May be required in mitosis for the processing of stalled or collapsed replication forks.
• KEGG Pathway:
  Homologous recombi.tion (hsa03440)
  Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Fanconi Anemia Pathway (R-HSA-6783310)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)

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	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]

10 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 Crossover junction endonuclease EME1 (EME1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Crossover junction endonuclease EME1 (EME1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Crossover junction endonuclease EME1 (EME1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Crossover junction endonuclease EME1 (EME1).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Crossover junction endonuclease EME1 (EME1).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Crossover junction endonuclease EME1 (EME1).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Crossover junction endonuclease EME1 (EME1).	[8]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Crossover junction endonuclease EME1 (EME1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Crossover junction endonuclease EME1 (EME1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Crossover junction endonuclease EME1 (EME1).	[13]

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 increases the methylation of Crossover junction endonuclease EME1 (EME1).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Crossover junction endonuclease EME1 (EME1).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Crossover junction endonuclease EME1 (EME1).	[14]

References

• [1] Rapid and accurate structure-based therapeutic peptide design using GPU accelerated thermodynamic integration.Proteins. 2019 Mar;87(3):236-244. doi: 10.1002/prot.25644. Epub 2019 Jan 4.
• [2] Functional evidence for Eme1 as a marker of cisplatin resistance.Int J Cancer. 2009 Jun 15;124(12):2997-3001. doi: 10.1002/ijc.24268.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [9] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.