Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ9PLNT)

• DOT Name: E3 ubiquitin-protein ligase RAD18 (RAD18)
• Synonyms: EC 2.3.2.27; Postreplication repair protein RAD18; hHR18; hRAD18; RING finger protein 73; RING-type E3 ubiquitin transferase RAD18
• Gene Name: RAD18
• Related Disease:
  Lung neoplasm
  Lung squamous cell carcinoma
  Carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Esophageal squamous cell carcinoma
  Fanconi anemia complementation group A
  Fanconi's anemia
  Glioma
  Lentivirus infection
  Oropharyngeal squamous cell carcinoma
  Squamous cell carcinoma
  Adult glioblastoma
  Glioblastoma multiforme
  Neoplasm
  Adenocarcinoma
  Advanced cancer
  Rectal carcinoma
• UniProt ID: RAD18_HUMAN
• PDB ID: 2MRE; 2MRF; 2Y43; 2YBF; 5VF0
• EC Number: 2.3.2.27
• Pfam ID: PF02037 ; PF13923
• Sequence:
  MDSLAESRWPPGLAVMKTIDDLLRCGICFEYFNIAMIIPQCSHNYCSLCIRKFLSYKTQC
  PTCCVTVTEPDLKNNRILDELVKSLNFARNHLLQFALESPAKSPASSSSKNLAVKVYTPV
  ASRQSLKQGSRLMDNFLIREMSGSTSELLIKENKSKFSPQKEASPAAKTKETRSVEEIAP
  DPSEAKRPEPPSTSTLKQVTKVDCPVCGVNIPESHINKHLDSCLSREEKKESLRSSVHKR
  KPLPKTVYNLLSDRDLKKKLKEHGLSIQGNKQQLIKRHQEFVHMYNAQCDALHPKSAAEI
  VREIENIEKTRMRLEASKLNESVMVFTKDQTEKEIDEIHSKYRKKHKSEFQLLVDQARKG
  YKKIAGMSQKTVTITKEDESTEKLSSVCMGQEDNMTSVTNHFSQSKLDSPEELEPDREED
  SSSCIDIQEVLSSSESDSCNSSSSDIIRDLLEEEEAWEASHKNDLQDTEISPRQNRRTRA
  AESAEIEPRNKRNRN
• Function: E3 ubiquitin-protein ligase involved in postreplication repair of UV-damaged DNA. Postreplication repair functions in gap-filling of a daughter strand on replication of damaged DNA. Associates to the E2 ubiquitin conjugating enzyme UBE2B to form the UBE2B-RAD18 ubiquitin ligase complex involved in mono-ubiquitination of DNA-associated PCNA on 'Lys-164'. Has ssDNA binding activity.
• Reactome Pathway:
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)
  Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung neoplasm	DISVARNB	Definitive	Genetic Variation	[1]
Lung squamous cell carcinoma	DISXPIBD	Definitive	Genetic Variation	[1]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Altered Expression	[6]
Fanconi's anemia	DISGW6Q8	Strong	Altered Expression	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[7]
Lentivirus infection	DISX17PY	Strong	Altered Expression	[7]
Oropharyngeal squamous cell carcinoma	DIS7D7QV	Strong	Biomarker	[8]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[6]
Adult glioblastoma	DISVP4LU	Disputed	Altered Expression	[9]
Glioblastoma multiforme	DISK8246	Disputed	Altered Expression	[9]
Neoplasm	DISZKGEW	Disputed	Biomarker	[10]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[12]
Rectal carcinoma	DIS8FRR7	Limited	Biomarker	[13]

14 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 E3 ubiquitin-protein ligase RAD18 (RAD18).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[18]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[26]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[27]
Fenthion	DMKEG49	Investigative	Fenthion decreases the expression of E3 ubiquitin-protein ligase RAD18 (RAD18).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of E3 ubiquitin-protein ligase RAD18 (RAD18).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase RAD18 (RAD18).	[24]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of E3 ubiquitin-protein ligase RAD18 (RAD18).	[28]

References

• [1] The association between RAD18 Arg302Gln polymorphism and the risk of human non-small-cell lung cancer.J Cancer Res Clin Oncol. 2008 Feb;134(2):211-7. doi: 10.1007/s00432-007-0272-3. Epub 2007 Jul 12.
• [2] Overexpression of DNA polymerase iota (Pol) in esophageal squamous cell carcinoma.Cancer Sci. 2012 Aug;103(8):1574-9. doi: 10.1111/j.1349-7006.2012.02309.x. Epub 2012 May 30.
• [3] Tumor suppressor miR-145 reverses drug resistance by directly targeting DNA damage-related gene RAD18 in colorectal cancer.Tumour Biol. 2015 Jul;36(7):5011-9. doi: 10.1007/s13277-015-3152-5. Epub 2015 Apr 27.
• [4] Single nucleotide polymorphism in the RAD18 gene and risk of colorectal cancer in the Japanese population.Oncol Rep. 2007 Nov;18(5):1171-5.
• [5] RAD18 promotes the migration and invasion of esophageal squamous cell cancer via the JNK-MMPs pathway.Cancer Lett. 2018 Mar 28;417:65-74. doi: 10.1016/j.canlet.2017.12.034. Epub 2018 Jan 3.
• [6] Np63 activates the Fanconi anemia DNA repair pathway and limits the efficacy of cisplatin treatment in squamous cell carcinoma.Nucleic Acids Res. 2016 Apr 20;44(7):3204-18. doi: 10.1093/nar/gkw036. Epub 2016 Jan 26.
• [7] High expression of RAD18 in glioma induces radiotherapy resistance via down-regulating P53 expression.Biomed Pharmacother. 2019 Apr;112:108555. doi: 10.1016/j.biopha.2019.01.016. Epub 2019 Feb 21.
• [8] Genomic Copy Number Variations Characterize the Prognosis of Both P16-Positive and P16-Negative Oropharyngeal Squamous Cell Carcinoma After Curative Resection.Medicine (Baltimore). 2015 Dec;94(50):e2187. doi: 10.1097/MD.0000000000002187.
• [9] Knockdown of RAD18 inhibits glioblastoma development.J Cell Physiol. 2019 Nov;234(11):21100-21112. doi: 10.1002/jcp.28713. Epub 2019 May 12.
• [10] Precision cancer therapy: profiting from tumor specific defects in the DNA damage tolerance system.Oncotarget. 2018 Apr 10;9(27):18832-18843. doi: 10.18632/oncotarget.24777. eCollection 2018 Apr 10.
• [11] Mutation analysis of Rad18 in human cancer cell lines and non small cell lung cancer tissues.J Exp Clin Cancer Res. 2009 Jul 25;28(1):106. doi: 10.1186/1756-9966-28-106.
• [12] RAD18 contributes to the migration and invasion of human cervical cancer cells via the interleukin? pathway.Mol Med Rep. 2019 Oct;20(4):3415-3423. doi: 10.3892/mmr.2019.10564. Epub 2019 Aug 6.
• [13] RAD18 may function as a predictor of response to preoperative concurrent chemoradiotherapy in patients with locally advanced rectal cancer through caspase-9-caspase-3-dependent apoptotic pathway.Cancer Med. 2019 Jun;8(6):3094-3104. doi: 10.1002/cam4.2203. Epub 2019 Apr 29.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] 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.
• [16] 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.
• [17] Exploring pradimicin-IRD antineoplastic mechanisms and related DNA repair pathways. Chem Biol Interact. 2023 Feb 1;371:110342. doi: 10.1016/j.cbi.2023.110342. Epub 2023 Jan 10.
• [18] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [19] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [20] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [21] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [27] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [28] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [29] The cytotoxicity and genotoxicity of single and combined fenthion and terbufos treatments in human liver cells and zebrafish embryos. Sci Total Environ. 2021 Mar 1;758:143597. doi: 10.1016/j.scitotenv.2020.143597. Epub 2020 Nov 10.