BAP1

{{Short description|Protein-coding gene in the species Homo sapiens}}

BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) is a deubiquitinating enzyme that in humans is encoded by the BAP1 gene.{{cite journal | vauthors = 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 | title = BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression | journal = Oncogene | volume = 16 | issue = 9 | pages = 1097–112 | date = Mar 1998 | pmid = 9528852 | doi = 10.1038/sj.onc.1201861 | doi-access = | s2cid = 1019611 }}{{cite web | title = Entrez Gene: BAP1 BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8314}} BAP1 encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its deubiquitinase activity. Recent studies have shown that BAP1 and its fruit fly homolog, [http://flybase.org/reports/FBgn0262166.html 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.{{cite journal | vauthors = Gaytán de Ayala Alonso A, Gutiérrez L, Fritsch C, Papp B, Beuchle D, Müller J | title = A genetic screen identifies novel polycomb group genes in Drosophila | journal = Genetics | volume = 176 | issue = 4 | pages = 2099–108 | date = Aug 2007 | pmid = 17717194 | pmc = 1950617 | doi = 10.1534/genetics.107.075739 }}

Nomenclature

BAP1 is also known as:

UniProt name: [https://www.uniprot.org/uniprot/Q92560 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 ([http://flybase.org/reports/FBgn0261823.html Asx] in fruit flies){{cite journal | vauthors = Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, Wilm M, Muir TW, Müller J | title = Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB | journal = Nature | volume = 465 | issue = 7295 | pages = 243–7 | date = May 2010 | pmid = 20436459 | pmc = 3182123 | doi = 10.1038/nature08966 | bibcode = 2010Natur.465..243S }}{{cite journal | vauthors = Sowa ME, Bennett EJ, Gygi SP, Harper JW | title = Defining the human deubiquitinating enzyme interaction landscape | journal = Cell | volume = 138 | issue = 2 | pages = 389–403 | date = Jul 2009 | pmid = 19615732 | pmc = 2716422 | doi = 10.1016/j.cell.2009.04.042 }} BAP1 has also been shown to associate with other factors involved in chromatin modulation and transcriptional regulation, such as Host cell factor C1,{{cite journal | vauthors = Machida YJ, Machida Y, Vashisht AA, Wohlschlegel JA, Dutta A | title = The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1 | journal = The Journal of Biological Chemistry | volume = 284 | issue = 49 | pages = 34179–88 | date = Dec 2009 | pmid = 19815555 | pmc = 2797188 | doi = 10.1074/jbc.M109.046755 | doi-access = free }}{{cite journal | vauthors = Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M, Lee J, Liu J, O'Rourke K, Dixit VM, Wilson AC | title = Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1 | journal = Molecular and Cellular Biology | volume = 29 | issue = 8 | pages = 2181–92 | date = Apr 2009 | pmid = 19188440 | pmc = 2663315 | doi = 10.1128/MCB.01517-08 }}{{cite journal | vauthors = Yu H, Mashtalir N, Daou S, Hammond-Martel I, Ross J, Sui G, Hart GW, Rauscher FJ, Drobetsky E, Milot E, Shi Y, Affar el B | title = The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression | journal = Molecular and Cellular Biology | volume = 30 | issue = 21 | pages = 5071–85 | date = Nov 2010 | pmid = 20805357 | pmc = 2953049 | doi = 10.1128/MCB.00396-10 }} 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, 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.{{cite journal | vauthors = Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, Wilkinson KD | title = BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization | journal = Cancer Research | volume = 68 | issue = 17 | pages = 6953–62 | date = Sep 2008 | pmid = 18757409 | pmc = 2736608 | doi = 10.1158/0008-5472.CAN-08-0365 }}
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.{{cite journal | vauthors = Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM | title = Frequent mutation of BAP1 in metastasizing uveal melanomas | journal = Science | volume = 330 | issue = 6009 | pages = 1410–3 | date = Dec 2010 | pmid = 21051595 | pmc = 3087380 | doi = 10.1126/science.1194472 | bibcode = 2010Sci...330.1410H }} 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,.{{cite journal | vauthors = 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 | title = The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma | journal = Nature Genetics | volume = 43 | issue = 7 | pages = 668–72 | date = Jul 2011 | pmid = 21642991 | doi = 10.1038/ng.855 | pmc = 4643098 }}
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.{{cite journal | vauthors = 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 | title = BAP1 loss defines a new class of renal cell carcinoma | journal = Nature Genetics | volume = 44 | issue = 7 | pages = 751–9 | date = Jul 2012 | pmid = 22683710 | doi = 10.1038/ng.2323 | pmc=3788680}}

= BAP1 tumor predisposition syndrome=

Two studies used genome sequencing independently to identify germline mutations in BAP1 in families with genetic predispositions to mesothelioma{{cite journal | vauthors = 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 | title = Germline BAP1 mutations predispose to malignant mesothelioma | journal = Nature Genetics | volume = 43 | issue = 10 | pages = 1022–5 | date = Oct 2011 | pmid = 21874000 | pmc = 3184199 | doi = 10.1038/ng.912 }} and melanocytic skin tumors{{cite journal | vauthors = 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 | title = Germline mutations in BAP1 predispose to melanocytic tumors | journal = Nature Genetics | volume = 43 | issue = 10 | pages = 1018–21 | date = Oct 2011 | pmid = 21874003 | pmc = 3328403 | doi = 10.1038/ng.910 }} 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.{{cite journal | vauthors=Heydrich CE, Schneider KA, Rana Q |title=When to Consider Referral to a Genetic Counselor for Lesser Known Cancer Syndromes |journal=Contemporary Oncology |year=2015 |volume=7 |issue=1 |pages= 26–32}}

Further studies have identified germline BAP1 mutations associated with other cancers.{{cite journal | vauthors = Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill JB, Christopher BN, Boru G, Hovland P, Davidorf FH | title = Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers | journal = Journal of Medical Genetics | volume = 48 | issue = 12 | pages = 856–9 | date = Dec 2011 | pmid = 21941004 | doi = 10.1136/jmedgenet-2011-100156 | pmc = 3825099 }} These studies suggest that germline mutation of BAP1 results in a [http://omim.org/entry/614327 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.{{cite journal | vauthors = 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 | title = BAP1 immunohistochemistry predicts outcomes in a multi-institutional cohort with clear cell renal cell carcinoma | journal = The Journal of Urology | volume = 191 | issue = 3 | pages = 603–10 | date = Mar 2014 | pmid = 24076305 | doi = 10.1016/j.juro.2013.09.041 }}

BAP1

Nomenclature

Gene

Structure

Function

Role in disease

= Somatic mutations in cancer =

= BAP1 tumor predisposition syndrome=

Immunochemistry

Interactions

References

External links

Further reading