Open Access Articles- Top Results for BAP1


SymbolsBAP1 ; HUCEP-13; UCHL2
External IDsOMIM603089 MGI1206586 HomoloGene3421 IUPHAR: 2332 ChEMBL: 1293314 GeneCards: BAP1 Gene
EC number3.4.19.12
RNA expression pattern
File:PBB GE BAP1 201419 at tn.png
More reference expression data
RefSeq (mRNA)NM_004656NM_027088
RefSeq (protein)NP_004647NP_081364
Location (UCSC)Chr 3:
52.44 – 52.44 Mb
Chr 14:
31.25 – 31.26 Mb
PubMed search[1][2]

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]


BAP1 is also known as:


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


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.


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

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

Somatic mutations in cancer

BAP1 tumor predisposition syndrome

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.


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]


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 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]


  1. ^ a b c d Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA et al. (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. PMID 9528852. doi:10.1038/sj.onc.1201861. 
  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. PMC 1950617. PMID 17717194. doi:10.1534/genetics.107.075739. 
  4. ^ a b c Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S et al. (May 2010). "Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB". Nature 465 (7295): 243–7. PMC 3182123. PMID 20436459. doi:10.1038/nature08966. 
  5. ^ 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. PMC 2716422. PMID 19615732. doi:10.1016/j.cell.2009.04.042. 
  6. ^ 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. PMC 2797188. PMID 19815555. doi:10.1074/jbc.M109.046755. 
  7. ^ Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M, Lee J et al. (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. PMC 2663315. PMID 19188440. doi:10.1128/MCB.01517-08. 
  8. ^ Yu H, Mashtalir N, Daou S, Hammond-Martel I, Ross J, Sui G et al. (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. PMC 2953049. PMID 20805357. doi:10.1128/MCB.00396-10. 
  9. ^ Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG et al. (Sep 2008). "BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization". Cancer Research 68 (17): 6953–62. PMC 2736608. PMID 18757409. doi:10.1158/0008-5472.CAN-08-0365. 
  10. ^ Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA et al. (Dec 2010). "Frequent mutation of BAP1 in metastasizing uveal melanomas". Science 330 (6009): 1410–3. PMC 3087380. PMID 21051595. doi:10.1126/science.1194472. 
  11. ^ Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L et al. (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. PMID 21642991. doi:10.1038/ng.855. 
  12. ^ Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S et al. (Jul 2012). "BAP1 loss defines a new class of renal cell carcinoma". Nature Genetics 44 (7): 751–9. PMID 22683710. doi:10.1038/ng.2323. 
  13. ^ Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E et al. (Oct 2011). "Germline BAP1 mutations predispose to malignant mesothelioma". Nature Genetics 43 (10): 1022–5. PMC 3184199. PMID 21874000. doi:10.1038/ng.912. 
  14. ^ Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P et al. (Oct 2011). "Germline mutations in BAP1 predispose to melanocytic tumors". Nature Genetics 43 (10): 1018–21. PMC 3328403. PMID 21874003. doi:10.1038/ng.910. 
  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 et al. (Dec 2011). "Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers". Journal of Medical Genetics 48 (12): 856–9. PMID 21941004. doi:10.1136/jmedgenet-2011-100156. 
  17. ^ Kapur P, Christie A, Raman JD, Then MT, Nuhn P, Buchner A et al. (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. PMID 24076305. doi:10.1016/j.juro.2013.09.041. 
  18. ^ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Opthalmologica 88: 925-7.doi:10.1111/j.1755-3768.2010.4142.x: Wiley. 
  19. ^ a b "International Mouse Phenotyping Consortium". 
  20. ^ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V et al. (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337â€"42. PMC 3572410. PMID 21677750. doi:10.1038/nature10163. 
  21. ^ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. PMID 21677718. doi:10.1038/474262a. 
  22. ^ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9â€"13. PMID 17218247. doi:10.1016/j.cell.2006.12.018. 
  23. ^ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN et al. (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. PMID 23870131. doi:10.1016/j.cell.2013.06.022. 
  24. ^ a b "Infection and Immunity Immunophenotyping (3i) Consortium". 
  25. ^ a b "OBCD Consortium". 

Further reading