BAP1

BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)
Identifiers
Symbols	BAP1; DKFZp686N04275; FLJ35406; FLJ37180; HUCEP-13; KIAA0272; UCHL2
External IDs	OMIM: 603089 MGI: 1206586 HomoloGene: 3421 GeneCards: BAP1 Gene
EC number	3.4.19.12
Gene Ontology Molecular function • chromatin binding • ubiquitin thiolesterase activity • ubiquitin-specific protease activity • protein binding • peptidase activity • cysteine-type peptidase activity Cellular component • intracellular • nucleus • nucleolus • cytoplasm • PR-DUB complex • intracellular membrane-bounded organelle Biological process • regulation of cell growth • protein modification process • ubiquitin-dependent protein catabolic process • negative regulation of cell proliferation • chromatin modification • protein deubiquitination • monoubiquitinated histone H2A deubiquitination • regulation of cell cycle • protein K48-linked deubiquitination Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	8314	104416
Ensembl	ENSG00000163930	ENSMUSG00000021901
UniProt	Q92560	Q3TCR6
RefSeq (mRNA)	NM_004656	NM_027088.2
RefSeq (protein)	NP_004647	NP_081364.1
Location (UCSC)	Chr 3: 52.44 – 52.44 Mb	Chr 14: 32.06 – 32.07 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. 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, 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.

Nomenclature

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

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:

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

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) BAP1 has also been shown to associate with other factors involved in chromatin modulation and transcriptional regulation, such as Host cell factor C1, 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.

BAP1 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. In 2010, Exome sequencing identified inactivating mutations in BAP1 in 47% of Uveal melanomas, and BAP1 mutation was strongly associated with metastasis. 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. Shortly thereafter, BAP1 mutations were identified in aggressive Mesotheliomas with similar mutations as seen in melanomas.

Two studies used Genome sequencing independently to identify Germline mutations in BAP1 in families with Genetic predispositions to mesothelioma and melanocytic skin tumors Their results have been replicated by a third group. These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers.

Interactions

BAP1 has been shown to interact with

• AHCYL2
• ANAPC7
• ANKRD17
• ASXL1
• ASXL2
• BRCA1
• CBX1
• CBX3
• EIF4EBP3
• FOXK1
• FOXK2
• HAT1
• HCFC1
• HIST2H2AC
• HSPA2
• IPO4
• IPO5
• KDM1B
• OGT
• PPM1G
• PSME3
• RBBP7
• UBE2O

Further reading

• Harbour JW (2012). "The genetics of uveal melanoma: an emerging framework for targeted therapy". Pigment Cell Melanoma Res. doi:10.1111/j.1755-148X.2012.00979.x. PMID 22268848. 
• Carbone M, Yang H (2012). "Molecular Pathways: Targeting Mechanisms of Asbestos and Erionite Carcinogenesis in Mesothelioma". Clin Cancer Res. PMID 22065079. 
• Landreville S, Agapova OA, Matatall KA, Kneass ZT, Onken MD, Lee RS, Bowcock AM, Harbour JW (2012). "Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma". Clin Cancer Res 18 (2): 408-16. PMC 3261307. PMID 22038994. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3261307. 
• Goldstein AM (2011). "Germline BAP1 mutations and tumor susceptibility". Nat Genet 43 (10): 925-6. doi:10.1038/ng.956. PMID 21956388. 
• Materin MA, Faries M, Kluger HM (2011). "Molecular alternations in uveal melanoma". Curr Probl Cancer 5 (4): 211-24. doi:10.1016/j.currproblcancer.2011.07.004. PMID 21911184. 
• Zhou ZR, Zhang YH, Liu S, Song AX, Hu HY (2012). "Length of the active-site crossover loop defines the substrate specificity of ubiquitin C-terminal hydrolases for ubiquitin chains". Biochem J 441 (1): 143-9. PMID 21851340. 
• Eletr ZM, Wilkinson KD (2011). "An emerging model for BAP1's role in regulating cell cycle progression". Cell Biochem Biophys 60 (1-2): 3-11. PMC 3128820. PMID 21484256. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3128820. 
• Patel M, Smyth E, Chapman PB, Wolchok JD, Schwartz GK, Abramson DH, Carvajal RD (2011). "Therapeutic implications of the emerging molecular biology of uveal melanoma". Clin Cancer Res 17 (8): 2087-100. PMID 21444680. 
• Gieni RS, Ismail IH, Campbell S, Hendzel MJ (2011). "Polycomb group proteins in the DNA damage response: a link between radiation resistance and "stemness"". Cell Cycle 10 (6): 883-94. PMID 21346409. 
• Ismail IH, Andrin C, McDonald D, Hendzel MJ (2010). "BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair". J Cell Biol 191 (1): 45-60. PMC 2953429. PMID 20921134. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2953429. 
• Nishikawa H, Wu W, Koike A, Kojima R, Gomi H, Fukuda M, Ohta T (2009). "BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity". Cancer Res 69 (1): 111-9. PMID 19117993. 
• Jensen DE, Rauscher FJ 3rd (1999). "Defining biochemical functions for the BRCA1 tumor suppressor protein: analysis of the BRCA1 binding protein BAP1". Cancer Lett 143 Suppl 1: S13-7. PMID 10546591.