Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9NK6ZT)

• DOT Name: E3 ubiquitin-protein ligase BRE1A (RNF20)
• Synonyms: BRE1-A; hBRE1; EC 2.3.2.27; RING finger protein 20; RING-type E3 ubiquitin transferase BRE1A
• Gene Name: RNF20
• Related Disease:
  Nervous system disease
  Acute lymphocytic leukaemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Colorectal neoplasm
  Epithelial ovarian cancer
  leukaemia
  Leukemia
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Seminoma
  Clear cell renal carcinoma
• UniProt ID: BRE1A_HUMAN
• PDB ID: 5TRB; 8GUI; 8GUJ; 8IEJ
• EC Number: 2.3.2.27
• Pfam ID: PF00097
• Sequence:
  MSGIGNKRAAGEPGTSMPPEKKAAVEDSGTTVETIKLGGVSSTEELDIRTLQTKNRKLAE
  MLDQRQAIEDELREHIEKLERRQATDDASLLIVNRYWSQFDENIRIILKRYDLEQGLGDL
  LTERKALVVPEPEPDSDSNQERKDDRERGEGQEPAFSFLATLASSSSEEMESQLQERVES
  SRRAVSQIVTVYDKLQEKVELLSRKLNSGDNLIVEEAVQELNSFLAQENMRLQELTDLLQ
  EKHRTMSQEFSKLQSKVETAESRVSVLESMIDDLQWDIDKIRKREQRLNRHLAEVLERVN
  SKGYKVYGAGSSLYGGTITINARKFEEMNAELEENKELAQNRLCELEKLRQDFEEVTTQN
  EKLKVELRSAVEQVVKETPEYRCMQSQFSVLYNESLQLKAHLDEARTLLHGTRGTHQHQV
  ELIERDEVSLHKKLRTEVIQLEDTLAQVRKEYEMLRIEFEQTLAANEQAGPINREMRHLI
  SSLQNHNHQLKGEVLRYKRKLREAQSDLNKTRLRSGSALLQSQSSTEDPKDEPAELKPDS
  EDLSSQSSASKASQEDANEIKSKRDEEERERERREKEREREREREKEKEREREKQKLKES
  EKERDSAKDKEKGKHDDGRKKEAEIIKQLKIELKKAQESQKEMKLLLDMYRSAPKEQRDK
  VQLMAAEKKSKAELEDLRQRLKDLEDKEKKENKKMADEDALRKIRAVEEQIEYLQKKLAM
  AKQEEEALLSEMDVTGQAFEDMQEQNIRLMQQLREKDDANFKLMSERIKSNQIHKLLKEE
  KEELADQVLTLKTQVDAQLQVVRKLEEKEHLLQSNIGTGEKELGLRTQALEMNKRKAMEA
  AQLADDLKAQLELAQKKLHDFQDEIVENSVTKEKDMFNFKRAQEDISRLRRKLETTKKPD
  NVPKCDEILMEEIKDYKARLTCPCCNMRKKDAVLTKCFHVFCFECVKTRYDTRQRKCPKC
  NAAFGANDFHRIYIG
• Function: Component of the RNF20/40 E3 ubiquitin-protein ligase complex that mediates monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1). H2BK120ub1 gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation (H3K4me and H3K79me, respectively). It thereby plays a central role inb histone code and gene regulation. The RNF20/40 complex forms a H2B ubiquitin ligase complex in cooperation with the E2 enzyme UBE2A or UBE2B; reports about the cooperation with UBE2E1/UBCH are contradictory. Required for transcriptional activation of Hox genes. Recruited to the MDM2 promoter, probably by being recruited by p53/TP53, and thereby acts as a transcriptional coactivator. Mediates the polyubiquitination of isoform 2 of PA2G4 in cancer cells leading to its proteasome-mediated degradation; (Microbial infection) Promotes the human herpesvirus 8 (KSHV) lytic cycle by inducing the expression of lytic viral genes including the latency switch gene RTA/ORF50.
• Tissue Specificity: Expressed in the normal brain and also in malignant gliomas (at protein level).
• Reactome Pathway:
  RHOBTB1 GTPase cycle (R-HSA-9013422)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[7]
leukaemia	DISS7D1V	Strong	Biomarker	[8]
Leukemia	DISNAKFL	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[7]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[3]
Seminoma	DIS3J8LJ	Strong	Biomarker	[9]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of E3 ubiquitin-protein ligase BRE1A (RNF20).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase BRE1A (RNF20).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase BRE1A (RNF20).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase BRE1A (RNF20).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of E3 ubiquitin-protein ligase BRE1A (RNF20).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase BRE1A (RNF20).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of E3 ubiquitin-protein ligase BRE1A (RNF20).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase BRE1A (RNF20).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of E3 ubiquitin-protein ligase BRE1A (RNF20).	[19]

References

• [1] RNF20 controls astrocytic differentiation through epigenetic regulation of STAT3 in the developing brain.Cell Death Differ. 2018 Feb;25(2):294-306. doi: 10.1038/cdd.2017.157. Epub 2017 Oct 6.
• [2] The HDAC inhibitor panobinostat (LBH589) exerts in vivo anti-leukaemic activity against MLL-rearranged acute lymphoblastic leukaemia and involves the RNF20/RNF40/WAC-H2B ubiquitination axis.Leukemia. 2018 Feb;32(2):323-331. doi: 10.1038/leu.2017.216. Epub 2017 Jul 10.
• [3] Role of RNF20 in cancer development and progression - a comprehensive review.Biosci Rep. 2018 Jul 12;38(4):BSR20171287. doi: 10.1042/BSR20171287. Print 2018 Aug 31.
• [4] RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer.Cell Death Differ. 2017 Apr;24(4):694-704. doi: 10.1038/cdd.2016.126. Epub 2017 Feb 3.
• [5] RNF20 Links Histone H2B Ubiquitylation with Inflammation and Inflammation-Associated Cancer.Cell Rep. 2016 Feb 16;14(6):1462-1476. doi: 10.1016/j.celrep.2016.01.020. Epub 2016 Feb 4.
• [6] Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers.Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3443-8. doi: 10.1073/pnas.0712384105. Epub 2008 Feb 25.
• [7] Early Loss of Histone H2B Monoubiquitylation Alters Chromatin Accessibility and Activates Key Immune Pathways That Facilitate Progression of Ovarian Cancer.Cancer Res. 2019 Feb 15;79(4):760-772. doi: 10.1158/0008-5472.CAN-18-2297. Epub 2018 Dec 18.
• [8] Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia.Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3901-6. doi: 10.1073/pnas.1301045110. Epub 2013 Feb 14.
• [9] Deficiency in mammalian histone H2B ubiquitin ligase Bre1 (Rnf20/Rnf40) leads to replication stress and chromosomal instability.Cancer Res. 2012 Apr 15;72(8):2111-9. doi: 10.1158/0008-5472.CAN-11-2209. Epub 2012 Feb 21.
• [10] RNF20 Suppresses Tumorigenesis by Inhibiting the SREBP1c-PTTG1 Axis in Kidney Cancer.Mol Cell Biol. 2017 Oct 27;37(22):e00265-17. doi: 10.1128/MCB.00265-17. Print 2017 Nov 15.
• [11] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [14] 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.
• [15] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [16] 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.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] 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.