Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS8G0EN)

• DOT Name: Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1)
• Synonyms: EC 3.4.19.12; BRCA1-associated protein 1; Cerebral protein 6
• Gene Name: BAP1
• Related Disease:
  BAP1-related tumor predisposition syndrome
  Kury-Isidor syndrome
  Renal cell carcinoma
• UniProt ID: BAP1_HUMAN
• PDB ID: 7VPW; 8H1T; 8SVF
• EC Number: 3.4.19.12
• Pfam ID: PF01088 ; PF18031
• Sequence:
  MNKGWLELESDPGLFTLLVEDFGVKGVQVEEIYDLQSKCQGPVYGFIFLFKWIEERRSRR
  KVSTLVDDTSVIDDDIVNNMFFAHQLIPNSCATHALLSVLLNCSSVDLGPTLSRMKDFTK
  GFSPESKGYAIGNAPELAKAHNSHARPEPRHLPEKQNGLSAVRTMEAFHFVSYVPITGRL
  FELDGLKVYPIDHGPWGEDEEWTDKARRVIMERIGLATAGEPYHDIRFNLMAVVPDRRIK
  YEARLHVLKVNRQTVLEALQQLIRVTQPELIQTHKSQESQLPEESKSASNKSPLVLEANR
  APAASEGNHTDGAEEAAGSCAQAPSHSPPNKPKLVVKPPGSSLNGVHPNPTPIVQRLPAF
  LDNHNYAKSPMQEEEDLAAGVGRSRVPVRPPQQYSDDEDDYEDDEEDDVQNTNSALRYKG
  KGTGKPGALSGSADGQLSVLQPNTINVLAEKLKESQKDLSIPLSIKTSSGAGSPAVAVPT
  HSQPSPTPSNESTDTASEIGSAFNSPLRSPIRSANPTRPSSPVTSHISKVLFGEDDSLLR
  VDCIRYNRAVRDLGPVISTGLLHLAEDGVLSPLALTEGGKGSSPSIRPIQGSQGSSSPVE
  KEVVEATDSREKTGMVRPGEPLSGEKYSPKELLALLKCVEAEIANYEACLKEEVEKRKKF
  KIDDQRRTHNYDEFICTFISMLAQEGMLANLVEQNISVRRRQGVSIGRLHKQRKPDRRKR
  SRPYKAKRQ
• Function: Deubiquitinating enzyme that plays a key role in chromatin by mediating deubiquitination of histone H2A and HCFC1. Catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1). Does not deubiquitinate monoubiquitinated histone H2B. Acts as a regulator of cell growth by mediating deubiquitination of HCFC1 N-terminal and C-terminal chains, with some specificity toward 'Lys-48'-linked polyubiquitin chains compared to 'Lys-63'-linked polyubiquitin chains. Deubiquitination of HCFC1 does not lead to increase stability of HCFC1. Interferes with the BRCA1 and BARD1 heterodimer activity by inhibiting their ability to mediate ubiquitination and autoubiquitination. It however does not mediate deubiquitination of BRCA1 and BARD1. Able to mediate autodeubiquitination via intramolecular interactions to couteract monoubiquitination at the nuclear localization signal (NLS), thereby protecting it from cytoplasmic sequestration. Acts as a tumor suppressor.
• Tissue Specificity: Highly expressed in testis, placenta and ovary. Expressed in breast.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway:
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  UCH proteinases (R-HSA-5689603)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
BAP1-related tumor predisposition syndrome	DISO4FCC	Definitive	Autosomal dominant	[1]
Kury-Isidor syndrome	DIS8ETF8	Strong	Autosomal dominant	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Autosomal dominant	[3]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Olaparib	DM8QB1D	Approved	Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1) increases the response to substance of Olaparib.	[15]
Afimoxifene	DMFORDT	Phase 2	Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1) affects the response to substance of Afimoxifene.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[5]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[13]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the expression of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[8]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[8]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[11]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1).	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] 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.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] 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.
• [7] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [8] 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.
• [9] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [10] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [11] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [12] Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J. 2019 Jan 15;9(2):4. doi: 10.1038/s41408-018-0165-5.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] BAP1 loss defines a new class of renal cell carcinoma. Nat Genet. 2012 Jun 10;44(7):751-9. doi: 10.1038/ng.2323.
• [16] Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2730-5. doi: 10.1073/pnas.1018872108. Epub 2011 Apr 11.