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

2017-08-01   Assunta De Rienzo , Joseph R. Testa 

Identity

HGNC
LOCATION
3p21.1
LOCUSID
ALIAS
HUCEP-13,UCHL2,hucep-6
FUSION GENES

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.

Proteins

Atlas Image
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.
In the cytoplasm, BAP1 has recently been shown to localize at the endoplasmic reticulum, where it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3). This binding modulates calcium (Ca2+) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis.

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.
Heterozygous germline mutations of Bap1 in mice predispose to tumor formation, providing in vivo evidence that Bap1 Is a bona fide tumor suppressor. Bap1+/- mice followed for up to 20 months of age demonstrated that haploinsufficient mutant mice exhibited a markedly higher incidence and accelerated onset of asbestos-induced malignant mesothelioma when compared with similarly-exposed wild-type littermates.

Implicated in

Entity name
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 name
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 name
Malignant Pleural Mesothelioma (MPM)
Note
MPM is a lethal disease resistant to most current therapies. In 2011, two independent investigations identified somatic BAP1 mutations in sporadic MPMs, and one report also identified families with MPMs resulting from germline mutations of BAP1. To date, BAP1 mutations have been found in 47-67% of sporadic MPM tumors, with 20-25% involving truncating point mutations and the remainder involving exonic deletions. The mutations occur mostly in epithelioid MPM (and many peritoneal mesotheliomas) and no significant correlation has been found between somatic mutation in BAP1 and gender, exposure to asbestos, or survival.
Fusion protein
Identified in pleural malignant mesothelioma specimens by RNA-seq data analysis:
BAP1 (3p21.1) / CCDC66 (3p14.3) (validated by Sanger sequencing)
BAP1 (3p21.1) / TNNC1 (3p21.1)
BAP1 (3p21.1) / PBRM1 3p21.1 (validated by Sanger sequencing)
Entity name
Familial Mesothelioma
Note
Inactivating somatic mutations of BAP1 have been reported in nearly 85% of metastasizing uveal melanomas, the most common primary cancer of the eye and a tumor type with a strong propensity for fatal metastasis. More than one half of the mutations were predicted to cause premature protein termination, and about 20% affected BAP1s ubiquitin carboxyl-terminal hydrolase domain.
Entity name
Cutaneous Melanoma
Note
Somatic mutations have been observed in about 5% of spontaneous cutaneous melanomas and 10% of atypical Spitz tumors.
Entity name
Clear Cell Renal Cell Carcinoma
Note
BAP1 is inactivated in about 15% of clear cell renal cell carcinomas (ccRCCs). Notably, BAP1 loss is a poor prognostic indicator in ccRCC, being associated with high tumor grade.
Entity name
Intrahepatic Cholangiocarcinoma
Note
Somatic BAP1 mutations were reported in 8 of 32 (25%) intrahepatic cholangiocarcinomas in a discovery screen and in 5 of 32 (16%) independent intrahepatic cholangiocarcinomas in a subsequent prevalence screen.
Entity name
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

Pubmed IDLast YearTitleAuthors
128002012003Novel tumor antigens identified by autologous antibody screening of childhood medulloblastoma cDNA libraries.Behrends U et al
286143052017BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation.Bononi A et al
216429912011The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.Bott M et al
81818521994Homozygous deletion, rearrangement and hypermethylation implicate chromosome region 3p14.3-3p21.3 in sporadic breast-cancer development.Buchhagen DL et al
269282272016Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Bueno R et al
164691602006Soya phytonutrients act on a panel of genes implicated with BRCA1 and BRCA2 oncosuppressors in human breast cell lines.Caëtano B et al
163418022005BAP1 and breast cancer risk.Coupier I et al
191973352009Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian families with high risk of breast cancer.Guénard F et al
210515952010Frequent mutation of BAP1 in metastasizing uveal melanomas.Harbour JW et al
124607382002Symposium overview: genetic polymorphisms in DNA repair and cancer risk.Hu JJ et al
95288521998BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.Jensen DE et al
106672171999BAP1, a candidate tumor suppressor protein that interacts with BRCA1.Jensen DE et al
241855092013Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.Jiao Y et al
268962812016Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations.Kadariya Y et al
124859962002Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains.Mallery DL et al
175253322007ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.Matsuoka S et al
191884402009Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1.Misaghi S et al
191179932009BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity.Nishikawa H et al
226837102012BAP1 loss defines a new class of renal cell carcinoma.Peña-Llopis S et al
283426572017Targeting BAP1: a new paradigm for mesothelioma.Schunselaar LM et al
193675812010Identification of neuroglycan C and interacting partners as potential susceptibility genes for schizophrenia in a Southern Chinese population.So HC et al
218740002011Germline BAP1 mutations predispose to malignant mesothelioma.Testa JR et al
189508452009Evaluating new candidate SNPs as low penetrance risk factors in sporadic breast cancer: a two-stage Spanish case-control study.Vega A et al
187574092008BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.Ventii KH et al
218740032011Germline mutations in BAP1 predispose to melanocytic tumors.Wiesner T et al
249287832014Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma.Xu J et al

Other Information

Locus ID:

NCBI: 8314
MIM: 603089
HGNC: 950
Ensembl: ENSG00000163930

Variants:

dbSNP: 8314
ClinVar: 8314
TCGA: ENSG00000163930
COSMIC: BAP1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000163930ENST00000296288F8W6N3
ENSG00000163930ENST00000460680Q92560
ENSG00000163930ENST00000460680A0A024R305
ENSG00000163930ENST00000469613H7C4V7
ENSG00000163930ENST00000470173C9J7L9
ENSG00000163930ENST00000478368H0Y8E8
ENSG00000163930ENST00000490917F8WEY5
ENSG00000163930ENST00000615113Q96TC6

Expression (GTEx)

0
50
100
150
200
250

Pathways

PathwaySourceExternal ID
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
DNA RepairREACTOMER-HSA-73894
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
DNA Double Strand Break ResponseREACTOMER-HSA-5693606
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksREACTOMER-HSA-5693565
DeubiquitinationREACTOMER-HSA-5688426
UCH proteinasesREACTOMER-HSA-5689603

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
210515952010Frequent mutation of BAP1 in metastasizing uveal melanomas.389
226837102012BAP1 loss defines a new class of renal cell carcinoma.276
218740002011Germline BAP1 mutations predispose to malignant mesothelioma.267
204364592010Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB.244
218740032011Germline mutations in BAP1 predispose to melanocytic tumors.195
216429912011The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.193
241855092013Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.183
228785002012Loss of the tumor suppressor BAP1 causes myeloid transformation.137
219410042011Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.124
233331142013Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation.124

Citation

Assunta De Rienzo ; Joseph R. Testa

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

Atlas Genet Cytogenet Oncol Haematol. 2017-08-01

Online version: http://atlasgeneticsoncology.org/gene/755/bap1-(brca1-associated-protein-1-(ubiquitin-carboxy-terminal-hydrolase))

Historical Card

2009-09-01 BAP1 (BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)) by  Frédéric Guénard,Francine Durocher 

Cancer Genomics Laboratory, Oncology, Molecular Endocrinology Research Centre, CRCHUL, CHUQ, Laval University, Québec, G1V 4G2, Canada