BAP1

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BAP1
Identifiers
Aliases BAP1, HUCEP-13, UCHL2, hucep-6, BRCA1 associated protein 1
External IDs MGI: 1206586 HomoloGene: 3421 GeneCards: BAP1
RNA expression pattern
PBB GE BAP1 201419 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_004656

NM_027088

RefSeq (protein)

NP_004647

NP_081364.1
NP_081364

Location (UCSC) Chr 3: 52.4 – 52.41 Mb Chr 14: 31.25 – 31.26 Mb
PubMed search [1] [2]
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.[3][4] BAP1 encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its deubiquitinase activity.[3] 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.[5]

Nomenclature[edit]

BAP1 is also known as:

Gene[edit]

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

Structure[edit]

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

  1. 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.
  2. a unique linker region, which includes a Host cell factor C1 binding domain at residues 356-385.
  3. 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[edit]

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)[6][7] BAP1 has also been shown to associate with other factors involved in chromatin modulation and transcriptional regulation, such as Host cell factor C1,[8][9][10] which acts as an adaptor to couple E2F transcription factors to chromatin-modifying complexes during cell cycle progression.

Role in disease[edit]

In cancer, BAP1 can function both as a Tumor suppressor and as a Metastasis suppressor.

Somatic mutations in cancer[edit]

BAP1 tumor predisposition syndrome[edit]

Two studies used Genome sequencing independently to identify Germline mutations in BAP1 in families with genetic predispositions to mesothelioma[15] and melanocytic skin tumors[16] 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.[17] Further studies have identified germline BAP1 mutations associated with other cancers.[18] These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers.

Immunochemistry[edit]

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.[19]

Interactions[edit]

BAP1 has been shown to interact with

Model organisms[edit]

Model organisms have been used in the study of BAP1 function. A conditional knockout mouse line called Bap1tm1a(EUCOMM)Hmgu was generated at the Wellcome Trust Sanger Institute.[20] Male and female animals underwent a standardized phenotypic screen[21] to determine the effects of deletion.[22][23][24][25] Additional screens performed: - In-depth immunological phenotyping[26] - in-depth bone and cartilage phenotyping[27]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ a b c d 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. 
  4. ^ "Entrez Gene: BAP1 BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)". 
  5. ^ 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 1950617Freely accessible. PMID 17717194. 
  6. ^ a b c 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. doi:10.1038/nature08966. PMC 3182123Freely accessible. PMID 20436459. 
  7. ^ a b c d e f g h i j k l m n o p q r s t u 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 2716422Freely accessible. PMID 19615732. 
  8. ^ a b c d e f g h i j 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 2797188Freely accessible. PMID 19815555. 
  9. ^ 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 2663315Freely accessible. PMID 19188440. 
  10. ^ 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 (Nov 2010). "The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression". Molecular and Cellular Biology. 30 (21): 5071–85. doi:10.1128/MCB.00396-10. PMC 2953049Freely accessible. PMID 20805357. 
  11. ^ 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 2736608Freely accessible. PMID 18757409. 
  12. ^ 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. doi:10.1126/science.1194472. PMC 3087380Freely accessible. PMID 21051595. 
  13. ^ 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. PMID 21642991. 
  14. ^ 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. PMID 22683710. 
  15. ^ 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 3184199Freely accessible. PMID 21874000. 
  16. ^ 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 3328403Freely accessible. PMID 21874003. 
  17. ^ 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. 
  18. ^ 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. PMID 21941004. 
  19. ^ 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. 
  20. ^ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. 
  21. ^ a b "International Mouse Phenotyping Consortium". 
  22. ^ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410Freely accessible. PMID 21677750. 
  23. ^ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718. 
  24. ^ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  25. ^ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207Freely accessible. PMID 23870131. 
  26. ^ a b "Infection and Immunity Immunophenotyping (3i) Consortium". 
  27. ^ "OBCD Consortium". 

External links[edit]

Further reading[edit]