Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC8SDA3)

• DOT Name: E3 ubiquitin-protein ligase BRE1B (RNF40)
• Synonyms: BRE1-B; EC 2.3.2.27; 95 kDa retinoblastoma-associated protein; RBP95; RING finger protein 40; RING-type E3 ubiquitin transferase BRE1B
• Gene Name: RNF40
• Related Disease:
  Advanced cancer
  Autism
  Breast neoplasm
  Colitis
  Neoplasm
  Nephrogenic diabetes insipidus
  Schizophrenia
  Prostate cancer
  Prostate carcinoma
  Childhood kidney Wilms tumor
  Colorectal carcinoma
  Retinoblastoma
  Wilms tumor
• UniProt ID: BRE1B_HUMAN
• PDB ID: 8GUI; 8GUJ; 8IEJ
• EC Number: 2.3.2.27
• Pfam ID: PF00097
• Sequence:
  MSGPGNKRAAGDGGSGPPEKKLSREEKTTTTLIEPIRLGGISSTEEMDLKVLQFKNKKLA
  ERLEQRQACEDELRERIEKLEKRQATDDATLLIVNRYWAQLDETVEALLRCHESQGELSS
  APEAPGTQEGPTCDGTPLPEPGTSELRDPLLMQLRPPLSEPALAFVVALGASSSEEVELE
  LQGRMEFSKAAVSRVVEASDRLQRRVEELCQRVYSRGDSEPLSEAAQAHTRELGRENRRL
  QDLATQLQEKHHRISLEYSELQDKVTSAETKVLEMETTVEDLQWDIEKLRKREQKLNKHL
  AEALEQLNSGYYVSGSSSGFQGGQITLSMQKFEMLNAELEENQELANSRMAELEKLQAEL
  QGAVRTNERLKVALRSLPEEVVRETGEYRMLQAQFSLLYNESLQVKTQLDEARGLLLATK
  NSHLRHIEHMESDELGLQKKLRTEVIQLEDTLAQVRKEYEMLRIEFEQNLAANEQAGPIN
  REMRHLISSLQNHNHQLKGDAQRYKRKLREVQAEIGKLRAQASGSAHSTPNLGHPEDSGV
  SAPAPGKEEGGPGPVSTPDNRKEMAPVPGTTTTTTSVKKEELVPSEEDFQGITPGAQGPS
  SRGREPEARPKRELREREGPSLGPPPVASALSRADREKAKVEETKRKESELLKGLRAELK
  KAQESQKEMKLLLDMYKSAPKEQRDKVQLMAAERKAKAEVDELRSRIRELEERDRRESKK
  IADEDALRRIRQAEEQIEHLQRKLGATKQEEEALLSEMDVTGQAFEDMQEQNGRLLQQLR
  EKDDANFKLMSERIKANQIHKLLREEKDELGEQVLGLKSQVDAQLLTVQKLEEKERALQG
  SLGGVEKELTLRSQALELNKRKAVEAAQLAEDLKVQLEHVQTRLREIQPCLAESRAAREK
  ESFNLKRAQEDISRLRRKLEKQRKVEVYADADEILQEEIKEYKARLTCPCCNTRKKDAVL
  TKCFHVFCFECVRGRYEARQRKCPKCNAAFGAHDFHRIYIS
• 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 in 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; (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: Ubiquitously expressed. Expressed at higher level in testis, heart and pancreas, while it is only weakly expressed in lung, skeletal muscle and small intestine.
• Reactome Pathway: E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Colitis	DISAF7DD	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Nephrogenic diabetes insipidus	DISKNSJK	Strong	Biomarker	[6]
Schizophrenia	DISSRV2N	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	moderate	Biomarker	[7]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[7]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[4]
Retinoblastoma	DISVPNPB	Limited	Biomarker	[9]
Wilms tumor	DISB6T16	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of E3 ubiquitin-protein ligase BRE1B (RNF40).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase BRE1B (RNF40).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of E3 ubiquitin-protein ligase BRE1B (RNF40).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of E3 ubiquitin-protein ligase BRE1B (RNF40).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase BRE1B (RNF40).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of E3 ubiquitin-protein ligase BRE1B (RNF40).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase BRE1B (RNF40).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of E3 ubiquitin-protein ligase BRE1B (RNF40).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase BRE1B (RNF40).	[18]

References

• [1] 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.
• [2] Gene expression in blood is associated with risperidone response in children with autism spectrum disorders.Pharmacogenomics J. 2012 Oct;12(5):368-71. doi: 10.1038/tpj.2011.23. Epub 2011 Jun 7.
• [3] 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.
• [4] Loss of RNF40 Decreases NF-B Activity in Colorectal Cancer Cells and Reduces Colitis Burden in Mice.J Crohns Colitis. 2019 Mar 26;13(3):362-373. doi: 10.1093/ecco-jcc/jjy165.
• [5] 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.
• [6] E3 ubiquitin-protein ligases in rat kidney collecting duct: response to vasopressin stimulation and withdrawal.Am J Physiol Renal Physiol. 2011 Oct;301(4):F883-96. doi: 10.1152/ajprenal.00117.2011. Epub 2011 Jul 6.
• [7] Histone H2B ubiquitin ligases RNF20 and RNF40 in androgen signaling and prostate cancer cell growth.Mol Cell Endocrinol. 2012 Mar 5;350(1):87-98. doi: 10.1016/j.mce.2011.11.025. Epub 2011 Dec 2.
• [8] Induction of Rb-associated protein (RbAp46) by Wilms' tumor suppressor WT1 mediates growth inhibition.J Biol Chem. 1998 Oct 16;273(42):27047-50. doi: 10.1074/jbc.273.42.27047.
• [9] RbAp46 inhibits estrogen-stimulated progression of neoplastigenic breast epithelial cells.Anticancer Res. 2007 Sep-Oct;27(5A):3205-9.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [16] 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.
• [17] 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.
• [18] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.