BAP1

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BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) is a deubiquitinating enzyme that in humans is encoded by the BAP1 gene.[1][2] BAP1 encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its deubiquitinase activity.[1] 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.[3]

## Contents

* 1 Nomenclature
* 2 Gene
* 3 Structure
* 4 Function
* 5 Role in disease
* 5.1 Somatic mutations in cancer
* 5.2 BAP1 tumor predisposition syndrome
* 6 Immunochemistry
* 7 Interactions
* 8 Model organisms
* 9 References
* 10 External links
* 11 Further reading

## Nomenclature

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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

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

## Structure

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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

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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)[4][5] BAP1 has also been shown to associate with other factors involved in chromatin modulation and transcriptional regulation, such as Host cell factor C1,[6][7][8] which acts as an adaptor to couple E2F transcription factors to chromatin-modifying complexes during cell cycle progression.

## Role in disease

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

### Somatic mutations in cancer

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* BAP1 somatic mutations were identified in a small number of breast and lung cancer cell lines,[1] 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.[9]
* 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.[10] 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,.[11]
* 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. .[12]

### BAP1 tumor predisposition syndrome

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Two studies used Genome sequencing independently to identify Germline mutations in BAP1 in families with genetic predispositions to mesothelioma[13] and melanocytic skin tumors[14] 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.[15] Further studies have identified germline BAP1 mutations associated with other cancers.[16] These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers.

## Immunochemistry

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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.[17]

## Interactions

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BAP1 has been shown to interact with

* AHCYL2[5]
* ANAPC7[5]
* ANKRD17[5][6]
* ASXL1[4][5][6]
* ASXL2[5][6]
* BRCA1[1]
* CBX1[5]
* CBX3[5]
* EIF4EBP3[5]
* FOXK1[5][6]
* FOXK2[5][6]
* HAT1[5][6]
* HCFC1[5][6]
* HIST2H2AC[4]
* HSPA2[6]
* IPO4[5]
* IPO5[5]
* KDM1B[5][6]
* OGT[5]
* PPM1G[5]
* PSME3[5]
* RBBP7[5]
* UBE2O[5]

## Model organisms

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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.[18] Male and female animals underwent a standardized phenotypic screen[19] to determine the effects of deletion.[20][21][22][23] Additional screens performed: - In-depth immunological phenotyping[24] \- in-depth bone and cartilage phenotyping[25]

Bap1 knockout mouse phenotype  Characteristic | Phenotype

|

All data available at.[19][24]
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

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1. ↑ 1.0 1.1 1.2 1.3 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.
2. ↑ "Entrez Gene: BAP1 BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)".
3. ↑ 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.
4. ↑ 4.0 4.1 4.2 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 3182123. PMID 20436459.
5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 5.18 5.19 5.20 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.
6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 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.
7. ↑ 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.
8. ↑ 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 2953049. PMID 20805357.
9. ↑ 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.
10. ↑ 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 3087380. PMID 21051595.
11. ↑ 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.
12. ↑ 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.
13. ↑ 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.
14. ↑ 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.
15. ↑ 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.
16. ↑ 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.
17. ↑ 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.
18. ↑ 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.
19. ↑ 19.0 19.1 "International Mouse Phenotyping Consortium".
20. ↑ 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 3572410. PMID 21677750.
21. ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
22. ↑ 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.
23. ↑ 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 3717207. PMID 23870131.
24. ↑ 24.0 24.1 "Infection and Immunity Immunophenotyping (3i) Consortium".
25. ↑ "OBCD Consortium".

## External links

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

## Further reading

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* Harbour JW (Mar 2012). "The genetics of uveal melanoma: an emerging framework for targeted therapy". Pigment Cell & Melanoma Research. 25 (2): 171–81. doi:10.1111/j.1755-148X.2012.00979.x. PMC 4470256. PMID 22268848.
* Carbone M, Yang H (Feb 2012). "Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma". Clinical Cancer Research. 18 (3): 598–604. doi:10.1158/1078-0432.CCR-11-2259. PMC 3291331. PMID 22065079.
* Landreville S, Agapova OA, Matatall KA, Kneass ZT, Onken MD, Lee RS, Bowcock AM, Harbour JW (Jan 2012). "Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma". Clinical Cancer Research. 18 (2): 408–16. doi:10.1158/1078-0432.CCR-11-0946. PMC 3261307. PMID 22038994.
* Goldstein AM (Oct 2011). "Germline BAP1 mutations and tumor susceptibility". Nature Genetics. 43 (10): 925–6. doi:10.1038/ng.956. PMC 4117248. PMID 21956388.
* Materin MA, Faries M, Kluger HM (2011). "Molecular alternations in uveal melanoma". Current Problems in Cancer. 35 (4): 211–24. doi:10.1016/j.currproblcancer.2011.07.004. PMID 21911184.
* Zhou ZR, Zhang YH, Liu S, Song AX, Hu HY (Jan 2012). "Length of the active-site crossover loop defines the substrate specificity of ubiquitin C-terminal hydrolases for ubiquitin chains". The Biochemical Journal. 441 (1): 143–9. doi:10.1042/BJ20110699. PMID 21851340.
* Eletr ZM, Wilkinson KD (Jun 2011). "An emerging model for BAP1's role in regulating cell cycle progression". Cell Biochemistry and Biophysics. 60 (1–2): 3–11. doi:10.1007/s12013-011-9184-6. PMC 3128820. PMID 21484256.
* Patel M, Smyth E, Chapman PB, Wolchok JD, Schwartz GK, Abramson DH, Carvajal RD (Apr 2011). "Therapeutic implications of the emerging molecular biology of uveal melanoma". Clinical Cancer Research. 17 (8): 2087–100. doi:10.1158/1078-0432.CCR-10-3169. PMID 21444680.
* Gieni RS, Ismail IH, Campbell S, Hendzel MJ (Mar 2011). "Polycomb group proteins in the DNA damage response: a link between radiation resistance and "stemness"". Cell Cycle. 10 (6): 883–94. doi:10.4161/cc.10.6.14907. PMID 21346409.
* Ismail IH, Andrin C, McDonald D, Hendzel MJ (Oct 2010). "BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair". The Journal of Cell Biology. 191 (1): 45–60. doi:10.1083/jcb.201003034. PMC 2953429. PMID 20921134.
* Nishikawa H, Wu W, Koike A, Kojima R, Gomi H, Fukuda M, Ohta T (Jan 2009). "BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity". Cancer Research. 69 (1): 111–9. doi:10.1158/0008-5472.CAN-08-3355. PMID 19117993.
* Jensen DE, Rauscher FJ (Sep 1999). "Defining biochemical functions for the BRCA1 tumor suppressor protein: analysis of the BRCA1 binding protein BAP1". Cancer Letters. 143 Suppl 1: S13–7. doi:10.1016/s0304-3835(99)90004-6. PMID 10546591.