BAP1

BAP1
Identifiers
Aliases	BAP1, HUCEP-13, UCHL2, hucep-6, BRCA1 associated protein 1
External IDs	OMIM: 603089 MGI: 1206586 HomoloGene: 3421 GeneCards: BAP1
Gene location (Human)
Chr.	Chromosome 3 (human)[1]
End	52,410,008 bp[1]
Gene location (Mouse)
Chr.	Chromosome 14 (mouse)[2]
End	31,259,944 bp[2]
RNA expression pattern
	More reference expression data
Gene ontology
Molecular function	• peptidase activity; • hydrolase activity; • chromatin binding; • cysteine-type peptidase activity; • thiol-dependent ubiquitin-specific protease activity; • GO:0001948 protein binding;
Cellular component	• cytoplasm; • PR-DUB complex; • intracellular; • cell nucleus; • nucleoplasm; • cytosol;
Biological process	• ubiquitin-dependent protein catabolic process; • regulation of cell cycle; • negative regulation of cell proliferation; • proteolysis; • regulation of cell growth; • cellular protein modification process; • monoubiquitinated protein deubiquitination; • positive regulation of protein targeting to mitochondrion; • protein K48-linked deubiquitination; • monoubiquitinated histone H2A deubiquitination; • response to inorganic substance; • protein deubiquitination; • regulation of inflammatory response; • macrophage homeostasis; • regulation of cytokine production involved in inflammatory response; • chromatin organization;
	Sources:Amigo / QuickGO
Orthologs
	8314
	104416
	ENSG00000163930
	ENSMUSG00000021901
	Q92560
	Q99PU7
	NM_004656
	NM_027088
	NP_004647
	NP_081364
	Wikidata
View/Edit Human	View/Edit Mouse

BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) is a deubiquitinating enzyme that in humans is encoded by the BAP1 gene.[5][6] BAP1 encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its deubiquitinase activity.[5] Recent studies have shown that BAP1 and its fruit fly homolog, Calypso, are members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.[7]

Nomenclature

BAP1 is also known as:

UniProt name: Ubiquitin carboxyl-terminal hydrolase BAP1
ubiquitin carboxyl-terminal hydrolase like-2 (UCHL2)
human cerebral protein 6 (hucep 6)
human cerebral protein-13 (hucep-13)

Gene

In humans, BAP1 is encoded by the BAP1 gene located on the short arm of chromosome 3 (3p21.31-p21.2).

Structure

Human BAP1 is 729 amino acids long and has three domains:

a ubiquitin carboxyl-terminal hydrolase (UCH) N-terminus catalytic domain, which removes ubiquitin from ubiquitylated substrates: residues 1-240, with an active site comprising the Cysteine91, Alanine95, and Glycine178 residues.
a unique linker region, which includes a Host cell factor C1 binding domain at residues 356-385.
a C-terminal domain: residues 598-729, which includes a UCH37-like domain (ULD) at residues 675-693 and two Nuclear localization sequences at residues 656-661 and 717-722.

Function

In both Drosophila and humans, BAP1 functions as the catalytic subunit of the Polycomb repressive deubiquitinase (PR-DUB) complex, which controls homeobox genes by regulating the amount of ubiquitinated Histone H2A in Nucleosomes bound to their promoters. In flies and humans, the PR-DUB complex is formed through the interaction of BAP1 and ASXL1 (Asx in fruit flies)[8][9] BAP1 has also been shown to associate with other factors involved in chromatin modulation and transcriptional regulation, such as Host cell factor C1,[10][11][12] which acts as an adaptor to couple E2F transcription factors to chromatin-modifying complexes during cell cycle progression.

Role in disease

In cancer, BAP1 can function both as a tumor suppressor and as a metastasis suppressor.

Somatic mutations in cancer

BAP1 somatic mutations were identified in a small number of breast and lung cancer cell lines,[5] but BAP1 was first shown to act as a tumor suppressor in cultured cells, where its deubiquitinase (UCH) domain and nuclear localization sequences were required for BAP1 to suppress cell growth.[13]
In 2010, J. William Harbour and colleagues published a landmark article in Science, in which they used exome sequencing of patient tumor samples and identified inactivating mutations in BAP1 in 47% of uveal melanomas. They were also the first to show germline BAP1 mutations, and that BAP1 mutation was strongly associated with metastasis.[14] These mutations included multiple nonsense mutations and splice site mutations throughout the gene. missense mutations were only found within the UCH and ULD domains, further supporting the requirement for BAP1 catalytic function. This study also identified a germline mutation in one of the uveal melanoma patients, suggesting that, besides being a metastasis suppressor, BAP1 could predispose certain people to more aggressive uveal melanoma tumors.
BAP1 mutations have been identified in aggressive mesotheliomas with similar mutations as seen in melanomas,.[15]
Mutations in the tumor suppressor gene BAP1 occur in approximately 15% of clear cell renal cell carcinoma (CCRCC) cases. Sequencing efforts demonstrated worse outcomes in patients with BAP1 mutated clear cell renal cell carcinoma.[16]

BAP1 tumor predisposition syndrome

Two studies used genome sequencing independently to identify germline mutations in BAP1 in families with genetic predispositions to mesothelioma[17] and melanocytic skin tumors[18] The atypical melanocytic lesions resemble Spitz nevi and have been characterized as "atypical Spitz tumors" (ASTs), although they have a unique histology and exhibit both BRAF and BAP1 mutations.[19] Further studies have identified germline BAP1 mutations associated with other cancers.[20] These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers.

Immunochemistry

Immunohistochemistry for BAP1 is a prognostic biomarker to predict poor oncologic outcomes and adverse clinicopathological features in patients with non-metastatic clear cell renal cell carcinoma (CCRCC). BAP1 assessment using immunohistochemistry on needle biopsy may benefit preoperative risk stratification and guide treatment planning.[21]

Interactions

BAP1 has been shown to interact with

Model organisms

Model organisms have been used in the study of BAP1 function. A conditional knockout mouse line called Bap1^{tm1a(EUCOMM)Hmgu} was generated at the Wellcome Trust Sanger Institute.[22] Male and female animals underwent a standardized phenotypic screen[23] to determine the effects of deletion.[24][25][26][27] Additional screens performed: - In-depth immunological phenotyping[28] - in-depth bone and cartilage phenotyping[29]

*Bap1* knockout mouse phenotype
Characteristic	Phenotype
All data available at.[23][28]
Peripheral blood leukocytes 6 Weeks	Normal
Insulin	Normal
Haematology 6 Weeks	Normal
Homozygous viability at P14	Abnormal
Recessive lethal study	Abnormal
Body weight	Normal
Neurological assessment	Normal
Grip strength	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology 16 Weeks	Normal
Peripheral blood leukocytes 16 Weeks	Normal
Heart weight	Normal
Salmonella infection	Normal
Cytotoxic T Cell Function	Normal
Spleen Immunophenotyping	Normal
Mesenteric Lymph Node Immunophenotyping	Normal
Bone Marrow Immunophenotyping	Normal
Epidermal Immune Composition	Normal
Influenza Challenge	Normal
Trichuris Challenge	Normal

References

GRCh38: Ensembl release 89: ENSG00000163930 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000021901 - Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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 (Mar 1998). "BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression". Oncogene. 16 (9): 1097–112. doi:10.1038/sj.onc.1201861. PMID 9528852.
"Entrez Gene: BAP1 BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)".
Gaytán de Ayala Alonso A, Gutiérrez L, Fritsch C, Papp B, Beuchle D, Müller J (Aug 2007). "A genetic screen identifies novel polycomb group genes in Drosophila". Genetics. 176 (4): 2099–108. doi:10.1534/genetics.107.075739. PMC 1950617. PMID 17717194.
Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, Wilm M, Muir TW, Müller J (May 2010). "Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB". Nature. 465 (7295): 243–7. Bibcode:2010Natur.465..243S. doi:10.1038/nature08966. PMC 3182123. PMID 20436459.
Sowa ME, Bennett EJ, Gygi SP, Harper JW (Jul 2009). "Defining the human deubiquitinating enzyme interaction landscape". Cell. 138 (2): 389–403. doi:10.1016/j.cell.2009.04.042. PMC 2716422. PMID 19615732.
Machida YJ, Machida Y, Vashisht AA, Wohlschlegel JA, Dutta A (Dec 2009). "The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1". The Journal of Biological Chemistry. 284 (49): 34179–88. doi:10.1074/jbc.M109.046755. PMC 2797188. PMID 19815555.
Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M, Lee J, Liu J, O'Rourke K, Dixit VM, Wilson AC (Apr 2009). "Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1". Molecular and Cellular Biology. 29 (8): 2181–92. doi:10.1128/MCB.01517-08. PMC 2663315. PMID 19188440.
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Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, Wilkinson KD (Sep 2008). "BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization". Cancer Research. 68 (17): 6953–62. doi:10.1158/0008-5472.CAN-08-0365. PMC 2736608. PMID 18757409.
Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM (Dec 2010). "Frequent mutation of BAP1 in metastasizing uveal melanomas". Science. 330 (6009): 1410–3. Bibcode:2010Sci...330.1410H. doi:10.1126/science.1194472. PMC 3087380. PMID 21051595.
Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L, Creaney J, Lake RA, Zakowski MF, Reva B, Sander C, Delsite R, Powell S, Zhou Q, Shen R, Olshen A, Rusch V, Ladanyi M (Jul 2011). "The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma". Nature Genetics. 43 (7): 668–72. doi:10.1038/ng.855. PMC 4643098. PMID 21642991.
Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, Kinch L, Hambuch T, Jain S, Lotan Y, Margulis V, Sagalowsky AI, Summerour PB, Kabbani W, Wong SW, Grishin N, Laurent M, Xie XJ, Haudenschild CD, Ross MT, Bentley DR, Kapur P, Brugarolas J (Jul 2012). "BAP1 loss defines a new class of renal cell carcinoma". Nature Genetics. 44 (7): 751–9. doi:10.1038/ng.2323. PMC 3788680. PMID 22683710.
Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, Pass HI, Trusa S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Comertpay S, Tanji M, Gaudino G, Yang H, Carbone M (Oct 2011). "Germline BAP1 mutations predispose to malignant mesothelioma". Nature Genetics. 43 (10): 1022–5. doi:10.1038/ng.912. PMC 3184199. PMID 21874000.
Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, Windpassinger C, Wackernagel W, Loy S, Wolf I, Viale A, Lash AE, Pirun M, Socci ND, Rütten A, Palmedo G, Abramson D, Offit K, Ott A, Becker JC, Cerroni L, Kutzner H, Bastian BC, Speicher MR (Oct 2011). "Germline mutations in BAP1 predispose to melanocytic tumors". Nature Genetics. 43 (10): 1018–21. doi:10.1038/ng.910. PMC 3328403. PMID 21874003.
Heydrich CE, Schneider KA, Rana Q (2015). "When to Consider Referral to a Genetic Counselor for Lesser Known Cancer Syndromes". Contemporary Oncology. 7 (1): 26–32.
Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill JB, Christopher BN, Boru G, Hovland P, Davidorf FH (Dec 2011). "Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers". Journal of Medical Genetics. 48 (12): 856–9. doi:10.1136/jmedgenet-2011-100156. PMC 3825099. PMID 21941004.
Kapur P, Christie A, Raman JD, Then MT, Nuhn P, Buchner A, Bastian P, Seitz C, Shariat SF, Bensalah K, Rioux-Leclercq N, Xie XJ, Lotan Y, Margulis V, Brugarolas J (Mar 2014). "BAP1 immunohistochemistry predicts outcomes in a multi-institutional cohort with clear cell renal cell carcinoma". The Journal of Urology. 191 (3): 603–10. doi:10.1016/j.juro.2013.09.041. PMID 24076305.
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External links

Human BAP1 genome location and BAP1 gene details page in the UCSC Genome Browser.