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BAP1 (BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase))

Written2009-09Frédéric Guénard, Francine Durocher
Cancer Genomics Laboratory, Oncology, Molecular Endocrinology Research Centre, CRCHUL, CHUQ, Laval University, Québec, G1V 4G2, Canada

(Note : for Links provided by Atlas : click)

Identity

Other namesHUCEP-13
UCHL2
hucep-6
HGNC (Hugo) BAP1
LocusID (NCBI) 8314
Atlas_Id 755
Location 3p21.1
Location_base_pair Starts at 52435020 and ends at 52444121 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Fusion genes
(updated 2016)
BAP1 (3p21.1) / ZBTB1 (14q23.3)TOX4 (14q11.2) / BAP1 (3p21.1)

DNA/RNA

Description The gene spans 9.0 kb and is composed of 17 exons.
Transcription Transcription start is 115 bp upstream of first ATG of the BAP1 ORF.
Pseudogene No pseudogene reported.

Protein

 
  Structure of BAP1. BAP1 is a 729 aa protein. UCH, Ubiquitin C-terminal hydrolase; HBM, HCF-binding motif (NHNY sequence); NLS, Nuclear localization signal.
Description Human BAP1 is 729 amino acids with a molecular weight of 90 kDa. The amino-terminal 240 amino acids show homology to ubiquitin C-terminal hydrolases (UCH).
BAP1 also contains a region of extreme acidity (amino acids 396 to 408), multiple potential phosphorylation sites and N-linked glycosylation sites. The C-terminal region contains two putative nuclear localization signals.
BAP1 binds to the RING finger domain of BRCA1 through its carboxyl-terminal region (594-657 amino acids). Domain comprised by residues 182-365 of BAP1 interacts with the RING finger domain of BARD1. Interaction of BAP1 with HCF-1 (host cell factor 1; HCFC1) is dependent on the NHNY sequence resembling the HCF-binding motif (HBM).
Expression BAP1 is expressed in a variety of human adult tissues. High expression was detected in testis, placenta and ovary, with varying levels detected in other tissues. Expression of BAP1 in normal human breast tissue was also detected.
Analysis conducted in mice revealed that Bap1 expression is up-regulated in the breast during puberty, pregnancy and as a result of parity.
BAP1 mRNA level is significantly increased in MCF10a cell line following genistein treatment, an isoflavone found in soya and proposed to prevent breast cancer.
Localisation BAP1 is a nuclear-localized ubiquitin carboxy-terminal hydrolase.
Function BAP1 enhances BRCA1-mediated inhibition of breast cancer cell growth and may serve as a regulator/effector of BRCA1 growth control/differentiation pathways. BAP1 interacts with HCF-1, a transcriptional cofactor found in a number of important regulatory complexes. Bap1 may help to control cell proliferation by regulating HCF-1 protein levels and by associating with genes involved in the G1-S transition.
The BRCA1/BARD1 complex possess a dual E3 ubiquitin ligase activity, promotes its own ubiquitination and targets other proteins. Although BAP1 associates with BRCA1, it does not appear to function in the deubiquitylation of the BRCA1/BARD1 complex. BAP1 inhibits the E3 ligase activity of BRCA1/BARD1 by binding the RING finger domain of BARD1 and possesses deubiquitination activity toward ubiquitin chains catalyzed by BRCA1/BARD1.
BAP1 and BRCA1/BARD1 may coordinately regulate ubiquitination during the DNA damage response and the cell cycle, BAP1 being phosphorylated by ATM and ATR in response to DNA damage and BAP1 inhibition causing S-phase retardation.
It was also proposed that specific regions and UCH activity of BAP1 play an essential role in TCR.
Homology The amino-terminal 240 amino acids show significant homology to a class of thiol proteases, designated UCH, which are implicated in the proteolytic processing of ubiquitin.

Mutations

Note The mutation of a residue predicted to disrupt the helical nature of the extreme C-terminal region of BAP1 abolishes the BAP1/BRCA1 interaction.
BAP1 can suppress tumorigenicity of lung cancer cells in athymic nude mice.
Deubiquitinating activity and nuclear localization are both required for BAP1-mediated tumor suppression. Moreover, BAP1-mediated growth suppression is independent of wild-type BRCA1.
Squamous-cell carcinomas and large-cell undifferentiated carcinomas showed LOH for a 3p21-22 locus.
Large rearrangements, deletions, and missense mutations of the BAP1 locus have been found in lung and sporadic breast tumors and in lung cancer cell lines.

Implicated in

Note
Entity Breast cancer
Note A study conducted on high-risk breast cancer families from the French population revealed that the BAP1 gene does not appear to be commonly involved in high-risk breast cancer predisposition. These results were thereafter confirmed in a larger study conducted on families with high risk of breast cancer from the French Canadian population. These studies do not rule out the possibility that BAP1 alleles might be associated with moderate or low breast cancer risk.
Selected variations of the BAP1 gene were also excluded as low penetrance risk alleles in sporadic breast cancer carried from the Spanish population.
  
Entity Medulloblastoma
Note Medulloblastoma is a highly malignant tumor of the cerebellum. This disease with poor prognosis occurs mostly in children. A screen of cDNA libraries with autologous sera to identify antigen-specific immune responses associated with this agressive tumor type pointed to the BAP1 gene as a possible target of immune response.
  
Entity Schizophrenia
Note The BAP1 gene was excluded as a promizing candidate gene for schizophrenia in a fine mapping association study carried out on chromosome 3p, one of the regions showing strong evidence of linkage with schizophrenia.
  

Bibliography

Homozygous deletion, rearrangement and hypermethylation implicate chromosome region 3p14.3-3p21.3 in sporadic breast-cancer development.
Buchhagen DL, Qiu L, Etkind P.
Int J Cancer. 1994 May 15;57(4):473-9.
PMID 8181852
 
A novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.
Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, Ishov AM, Tommerup N, Vissing H, Sekido Y, Minna J, Borodovsky A, Schultz DC, Wilkinson KD, Maul GG, Barlev N, Berger SL, Prendergast GC, Rauscher FJ 3rd.
Oncogene 1998 Mar 5;16(9):1097-1112.
PMID 9528852
 
BAP1, a candidate tumor suppressor protein that interacts with BRCA1.
Jensen DE, Rauscher FJ 3rd.
Ann N Y Acad Sci 1999;886:191-194. (REVIEW)
PMID 10667217
 
Symposium overview: genetic polymorphisms in DNA repair and cancer risk.
Hu JJ, Mohrenweiser HW, Bell DA, Leadon SA, Miller MS.
Toxicol Appl Pharmacol 2002 Nov 15;185(1):64-73.
PMID 12460738
 
Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains.
Mallery DL, Vandenberg CJ, Hiom K.
EMBO J 2002 Dec 16;21(24):6755-6762.
PMID 12485996
 
Novel tumor antigens identified by autologous antibody screening of childhood medulloblastoma cDNA libraries.
Behrends U, Schneider I, Rossler S, Frauenknecht H, Golbeck A, Lechner B, Eigenstetter G, Zobywalski C, Muller-Weihrich S, Graubner U, Schmid I, Sackerer D, Spath M, Goetz C, Prantl F, Asmuss HP, Bise K, Mautner J.
Int J Cancer 2003 Aug 20;106(2):244-251.
PMID 12800201
 
BAP1 and breast cancer risk.
Coupier I, Cousin PY, Hughes D, Legoix-Ne P, Trehin A, Sinilnikova OM, Stoppa-Lyonnet D.
Fam Cancer 2005;4(4):273-277.
PMID 16341802
 
Soya phytonutrients act on a panel of genes implicated with BRCA1 and BRCA2 oncosuppressors in human breast cell lines.
Caetano B, Le Corre L, Chalabi N, Delort L, Bignon YJ, Bernard-Gallon DJ.
Br J Nutr 2006 Feb;95(2):406-413.
PMID 16469160
 
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.
Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J,Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ
Science 2007 May 25;316(5828):1160-1166.
PMID 17525332
 
BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.
Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, Wilkinson KD.
Cancer Res 2008 Sep 1;68(17):6953-6962.
PMID 18757409
 
Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian Families with high risk of breast cancer.
Guenard F, Labrie Y, Ouellette G, Joly Beauparlant C, Durocher F.
J Hum Genet 2009;54(3):152-161.
PMID 19197335
 
Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1.
Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M, Lee J, Liu J, O'Rourke K, Dixit VM, Wilson AC.
Mol Cell Biol 2009 Apr;29(8):2181-2192.
PMID 19188440
 
BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity.
Nishikawa H, Wu W, Koike A, Kojima R, Gomi H, Fukuda M, Ohta T.
Cancer Res 2009 Jan 1;69(1):111-119.
PMID 19117993
 
Identification of neuroglycan C and interacting partners as potential susceptibility genes for schizophrenia in a Southern Chinese population.
So HC, Fong PY, Chen RY, Hui TC, Ng MY, Cherny SS, Mak WW, Cheung EF, Chan RC, Chen EY, Li T, Sham PC.
Am J Med Genet B Neuropsychiatr Genet 2009 Apr 14. [Epub ahead of print]
PMID 19367581
 
Evaluating new candidate SNPs as low penetrance risk factors in sporadic breast cancer: a two-stage Spanish case-control study.
Vega A, Salas A, Milne RL, Carracedo B, Ribas G, Ruibal A, de Leon AC, Gonzalez-Hernandez A, Benitez J, Carracedo A.
Gynecol Oncol 2009 Jan;112(1):210-214.
PMID 18950845
 

Citation

This paper should be referenced as such :
Guénard, F ; Durocher, F
BAP1 (BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase))
Atlas Genet Cytogenet Oncol Haematol. 2010;14(7):670-672.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/BAP1ID755ch3p21.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 0 ]
  Skin: Spitz tumors

External links

Nomenclature
HGNC (Hugo)BAP1   950
Cards
AtlasBAP1ID755ch3p21
Entrez_Gene (NCBI)BAP1  8314  BRCA1 associated protein 1
GeneCards (Weizmann)BAP1
Ensembl hg19 (Hinxton)ENSG00000163930 [Gene_View]  chr3:52435020-52444121 [Contig_View]  BAP1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000163930 [Gene_View]  chr3:52435020-52444121 [Contig_View]  BAP1 [Vega]
ICGC DataPortalENSG00000163930
TCGA cBioPortalBAP1
AceView (NCBI)BAP1
Genatlas (Paris)BAP1
WikiGenes8314
SOURCE (Princeton)BAP1
Genomic and cartography
GoldenPath hg19 (UCSC)BAP1  -     chr3:52435020-52444121 -  3p21.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)BAP1  -     3p21.1   [Description]    (hg38-Dec_2013)
EnsemblBAP1 - 3p21.1 [CytoView hg19]  BAP1 - 3p21.1 [CytoView hg38]
Mapping of homologs : NCBIBAP1 [Mapview hg19]  BAP1 [Mapview hg38]
OMIM603089   614327   
Gene and transcription
Genbank (Entrez)AB002534 AF045581 AK092725 AK094499 AK225494
RefSeq transcript (Entrez)NM_004656
RefSeq genomic (Entrez)NC_000003 NC_018914 NG_031859 NT_022517 NW_004929309
Consensus coding sequences : CCDS (NCBI)BAP1
Cluster EST : UnigeneHs.106674 [ NCBI ]
CGAP (NCI)Hs.106674
Alternative Splicing GalleryENSG00000163930
Gene ExpressionBAP1 [ NCBI-GEO ]   BAP1 [ EBI - ARRAY_EXPRESS ]   BAP1 [ SEEK ]   BAP1 [ MEM ]
Gene Expression Viewer (FireBrowse)BAP1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8314
GTEX Portal (Tissue expression)BAP1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92560 (Uniprot)
NextProtQ92560  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ92560
Splice isoforms : SwissVarQ92560 (Swissvar)
Catalytic activity : Enzyme3.4.19.12 [ Enzyme-Expasy ]   3.4.19.123.4.19.12 [ IntEnz-EBI ]   3.4.19.12 [ BRENDA ]   3.4.19.12 [ KEGG ]   
PhosPhoSitePlusQ92560
Domains : Interpro (EBI)Peptidase_C12_UCH   
Domain families : Pfam (Sanger)Peptidase_C12 (PF01088)   
Domain families : Pfam (NCBI)pfam01088   
DMDM Disease mutations8314
Blocks (Seattle)BAP1
SuperfamilyQ92560
Human Protein AtlasENSG00000163930
Peptide AtlasQ92560
HPRD04366
IPIIPI00465087   IPI00908625   IPI00382831   IPI00796196   IPI00947312   IPI00946380   IPI00946816   
Protein Interaction databases
DIP (DOE-UCLA)Q92560
IntAct (EBI)Q92560
FunCoupENSG00000163930
BioGRIDBAP1
STRING (EMBL)BAP1
ZODIACBAP1
Ontologies - Pathways
QuickGOQ92560
Ontology : AmiGOregulation of cell growth  chromatin binding  thiol-dependent ubiquitin-specific protease activity  protein binding  nucleus  nucleoplasm  cytoplasm  cellular protein modification process  ubiquitin-dependent protein catabolic process  peptidase activity  negative regulation of cell proliferation  protein deubiquitination  PR-DUB complex  monoubiquitinated protein deubiquitination  monoubiquitinated histone H2A deubiquitination  regulation of cell cycle  protein K48-linked deubiquitination  positive regulation of protein targeting to mitochondrion  
Ontology : EGO-EBIregulation of cell growth  chromatin binding  thiol-dependent ubiquitin-specific protease activity  protein binding  nucleus  nucleoplasm  cytoplasm  cellular protein modification process  ubiquitin-dependent protein catabolic process  peptidase activity  negative regulation of cell proliferation  protein deubiquitination  PR-DUB complex  monoubiquitinated protein deubiquitination  monoubiquitinated histone H2A deubiquitination  regulation of cell cycle  protein K48-linked deubiquitination  positive regulation of protein targeting to mitochondrion  
NDEx Network
Atlas of Cancer Signalling NetworkBAP1
Wikipedia pathwaysBAP1
Orthology - Evolution
OrthoDB8314
GeneTree (enSembl)ENSG00000163930
Phylogenetic Trees/Animal Genes : TreeFamBAP1
Homologs : HomoloGeneBAP1
Homology/Alignments : Family Browser (UCSC)BAP1
Gene fusions - Rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerBAP1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)BAP1
dbVarBAP1
ClinVarBAP1
1000_GenomesBAP1 
Exome Variant ServerBAP1
ExAC (Exome Aggregation Consortium)BAP1 (select the gene name)
Genetic variants : HAPMAP8314
Genomic Variants (DGV)BAP1 [DGVbeta]
Mutations
ICGC Data PortalBAP1 
TCGA Data PortalBAP1 
Broad Tumor PortalBAP1
OASIS PortalBAP1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICBAP1 
intOGen PortalBAP1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
BioMutasearch BAP1
DgiDB (Drug Gene Interaction Database)BAP1
DoCM (Curated mutations)BAP1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)BAP1 (select a term)
intoGenBAP1
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)3:52435020-52444121  ENSG00000163930
CONAN: Copy Number AnalysisBAP1 
Mutations and Diseases : HGMDBAP1
OMIM603089    614327   
MedgenBAP1
Genetic Testing Registry BAP1
NextProtQ92560 [Medical]
TSGene8314
GENETestsBAP1
Huge Navigator BAP1 [HugePedia]
snp3D : Map Gene to Disease8314
BioCentury BCIQBAP1
ClinGenBAP1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD8314
Chemical/Pharm GKB GenePA25254
Clinical trialBAP1
Miscellaneous
canSAR (ICR)BAP1 (select the gene name)
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=BAP1
Probes
Litterature
PubMed125 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineBAP1
EVEXBAP1
GoPubMedBAP1
iHOPBAP1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu May 26 11:36:39 CEST 2016

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