View source for BAP1

{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{Infobox_gene}}
'''BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)''' is a [[deubiquitinating enzyme]] that in humans is encoded by the ''BAP1'' [[gene]].<ref name="pmid9528852">{{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 }}</ref><ref name="entrez">{{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}}</ref>  ''BAP1'' encodes an 80.4 [[Atomic mass unit|kDa]] [[Cell nucleus|nuclear-localizing]] protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its [[deubiquitinating enzyme|deubiquitinase]] activity.<ref name=pmid9528852/>  Recent studies have shown that ''BAP1'' and its [[Drosophila melanogaster|fruit fly]] homolog, [http://flybase.org/reports/FBgn0262166.html ''Calypso''], are members of the [[polycomb-group proteins]] (PcG) of highly conserved [[transcription (genetics)|transcriptional]] repressors required for long-term silencing of genes that regulate [[cell fate determination]], [[cell potency|stem cell pluripotency]], and other developmental processes.<ref name="pmid17717194">{{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 }}</ref>
== 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 (human)|chromosome 3]] (3p21.31-p21.2).
== Structure ==
Human BAP1 is 729 [[amino acid]]s long and has three [[domain (protein)|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 [[Cysteine]]91, [[Alanine]]95, and [[Glycine]]178 residues.
# a unique linker region, which includes a [[Host cell factor C1]] [[Protein-protein interaction|binding]] domain at residues 356-385.
# a [[C-terminal]] domain: residues 598-729, which includes a [[Ubiquitin carboxyl-terminal hydrolase L5|UCH37]]-like domain (ULD) at residues 675-693 and two [[Nuclear localization sequence]]s 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 [[Nucleosome]]s bound to their [[Promoter (genetics)|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 [[Drosophila melanogaster|fruit flies]])<ref name="pmid20436459">{{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 }}</ref><ref name="pmid19615732">{{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 }}</ref> BAP1 has also been shown to associate with other factors involved in chromatin modulation and transcriptional regulation, such as [[Host cell factor C1]],<ref name="pmid19815555">{{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 }}</ref><ref name="pmid19188440">{{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 }}</ref><ref name="pmid20805357">{{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 }}</ref> 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 mutation]]s were identified in a small number of breast and lung cancer cell lines,<ref name=pmid9528852/> but BAP1 was first shown to act as a [[tumor suppressor]] in cultured cells, where its [[Deubiquitinating enzyme|deubiquitinase]] (UCH) domain and [[nuclear localization sequence]]s were required for BAP1 to suppress cell growth.<ref name="pmid18757409">{{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 }}</ref>
* In 2010, [[J. William Harbour]] and colleagues published a landmark article in [[Science (journal)|Science]], in which they used [[exome sequencing]] of patient tumor samples and identified inactivating mutations in BAP1 in 47% of [[uveal melanoma]]s. They were also the first to show germline BAP1 mutations, and that BAP1 mutation was strongly associated with [[metastasis]].<ref name="pmid21051595">{{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 }}</ref>  These [[mutation]]s included multiple [[nonsense mutations]] and [[RNA splicing#Splicing errors|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 [[genetic predisposition|predispose]] certain people to more aggressive [[uveal melanoma]] tumors.
* BAP1 mutations have been identified in aggressive [[mesothelioma]]s with similar mutations as seen in melanomas,.<ref name="pmid21642991">{{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 }}</ref>
* 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.<ref name="doi.10.1038/ng.2323">{{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}}</ref>
=== BAP1 tumor predisposition syndrome===
Two studies used [[genome sequencing]] independently to identify [[germline mutation]]s in BAP1 in families with [[genetic predisposition]]s to [[mesothelioma]]<ref name="pmid21874000">{{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 }}</ref> and [[Melanocytic tumors of uncertain malignant potential|melanocytic skin tumors]]<ref name="pmid21874003">{{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 }}</ref> 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.<ref>{{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}}</ref>
Further studies have identified germline BAP1 mutations associated with other cancers.<ref name="pmid21941004">{{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 }}</ref>  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.<ref name="pmid24076305">{{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 }}</ref>
== Interactions ==
BAP1 has been shown to [[Protein-protein interaction|interact]] with
{{div col|colwidth=25em}}
* [[AHCYL2]]<ref name = pmid19615732/>
* [[ANAPC7]]<ref name = pmid19615732/>
* [[ANKRD17]]<ref name = pmid19615732/><ref name = pmid19815555/>
* [[ASXL1]]<ref name = pmid20436459/><ref name = pmid19615732/><ref name = pmid19815555/>
* [[Additional sex combs like 2, transcriptional regulator|ASXL2]]<ref name = pmid19615732/><ref name = pmid19815555/>
* [[BRCA1]]<ref name = pmid9528852/>
* [[CBX1]]<ref name = pmid19615732/>
* [[CBX3]]<ref name = pmid19615732/>
* [[EIF4EBP3]]<ref name = pmid19615732/>
* [[FOXK1]]<ref name = pmid19615732/><ref name = pmid19815555/>
* [[FOXK2]]<ref name = pmid19615732/><ref name = pmid19815555/>
* [[HAT1]]<ref name = pmid19615732/><ref name = pmid19815555/>
* [[HCFC1]]<ref name = pmid19615732/><ref name = pmid19815555/>
* [[HIST2H2AC]]<ref name = pmid20436459/>
* [[HSPA2]]<ref name = pmid19815555/>
* [[IPO4]]<ref name = pmid19615732/>
* [[IPO5]]<ref name = pmid19615732/>
* [[KDM1B]]<ref name = pmid19615732/><ref name = pmid19815555/>
* [[OGT (gene)|OGT]]<ref name = pmid19615732/>
* [[PPM1G]]<ref name = pmid19615732/>
* [[PSME3]]<ref name = pmid19615732/>
* [[RBBP7]]<ref name = pmid19615732/>
* [[UBE2O]]<ref name = pmid19615732/>
{{div col end}}
==References==
{{reflist|33em}}
==External links==
* {{UCSC gene info|BAP1}}
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Harbour JW | title = The genetics of uveal melanoma: an emerging framework for targeted therapy | journal = Pigment Cell & Melanoma Research | volume = 25 | issue = 2 | pages = 171–81 | date = Mar 2012 | pmid = 22268848 | doi = 10.1111/j.1755-148X.2012.00979.x | pmc = 4470256 }}
* {{cite journal | vauthors = Carbone M, Yang H | title = Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma | journal = Clinical Cancer Research | volume = 18 | issue = 3 | pages = 598–604 | date = Feb 2012 | pmid = 22065079 | doi = 10.1158/1078-0432.CCR-11-2259 | pmc = 3291331 }}
* {{cite journal | vauthors = Landreville S, Agapova OA, Matatall KA, Kneass ZT, Onken MD, Lee RS, Bowcock AM, Harbour JW | title = Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma | journal = Clinical Cancer Research | volume = 18 | issue = 2 | pages = 408–16 | date = Jan 2012 | pmid = 22038994 | pmc = 3261307 | doi = 10.1158/1078-0432.CCR-11-0946 }}
* {{cite journal | vauthors = Goldstein AM | title = Germline BAP1 mutations and tumor susceptibility | journal = Nature Genetics | volume = 43 | issue = 10 | pages = 925–6 | date = Oct 2011 | pmid = 21956388 | doi = 10.1038/ng.956 | pmc = 4117248 }}
* {{cite journal | vauthors = Materin MA, Faries M, Kluger HM | title = Molecular alternations in uveal melanoma | journal = Current Problems in Cancer | volume = 35 | issue = 4 | pages = 211–24 | year = 2011 | pmid = 21911184 | doi = 10.1016/j.currproblcancer.2011.07.004 }}
* {{cite journal | vauthors = Zhou ZR, Zhang YH, Liu S, Song AX, Hu HY | title = Length of the active-site crossover loop defines the substrate specificity of ubiquitin C-terminal hydrolases for ubiquitin chains | journal = The Biochemical Journal | volume = 441 | issue = 1 | pages = 143–9 | date = Jan 2012 | pmid = 21851340 | doi = 10.1042/BJ20110699 }}
* {{cite journal | vauthors = Eletr ZM, Wilkinson KD | title = An emerging model for BAP1's role in regulating cell cycle progression | journal = [[Cell Biochemistry and Biophysics]] | volume = 60 | issue = 1–2 | pages = 3–11 | date = Jun 2011 | pmid = 21484256 | pmc = 3128820 | doi = 10.1007/s12013-011-9184-6 }}
* {{cite journal | vauthors = Patel M, Smyth E, Chapman PB, Wolchok JD, Schwartz GK, Abramson DH, Carvajal RD | title = Therapeutic implications of the emerging molecular biology of uveal melanoma | journal = Clinical Cancer Research | volume = 17 | issue = 8 | pages = 2087–100 | date = Apr 2011 | pmid = 21444680 | doi = 10.1158/1078-0432.CCR-10-3169 | doi-access = free }}
* {{cite journal | vauthors = Gieni RS, Ismail IH, Campbell S, Hendzel MJ | title = Polycomb group proteins in the DNA damage response: a link between radiation resistance and "stemness" | journal = Cell Cycle | volume = 10 | issue = 6 | pages = 883–94 | date = Mar 2011 | pmid = 21346409 | doi = 10.4161/cc.10.6.14907 | doi-access = free }}
* {{cite journal | vauthors = Ismail IH, Andrin C, McDonald D, Hendzel MJ | title = BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair | journal = The Journal of Cell Biology | volume = 191 | issue = 1 | pages = 45–60 | date = Oct 2010 | pmid = 20921134 | pmc = 2953429 | doi = 10.1083/jcb.201003034 }}
* {{cite journal | vauthors = Nishikawa H, Wu W, Koike A, Kojima R, Gomi H, Fukuda M, Ohta T | title = BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity | journal = Cancer Research | volume = 69 | issue = 1 | pages = 111–9 | date = Jan 2009 | pmid = 19117993 | doi = 10.1158/0008-5472.CAN-08-3355 | doi-access = free }}
* {{cite journal | vauthors = Jensen DE, Rauscher FJ | title = Defining biochemical functions for the BRCA1 tumor suppressor protein: analysis of the BRCA1 binding protein BAP1 | journal = Cancer Letters | volume = 143 | pages = S13-7 | date = Sep 1999 | issue = Suppl 1 | pmid = 10546591 | doi = 10.1016/s0304-3835(99)90004-6 }}
{{refend}}
[[Category:Proteins]]