BAP1

BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) is a is_associated_with::deubiquitinating enzyme that in humans is encoded by the BAP1 is_associated_with::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 is_associated_with::polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate is_associated_with::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 is_associated_with::amino acids long and has three domains:


 * 1) a ubiquitin carboxyl-terminal hydrolase (UCH) is_associated_with::N-terminus catalytic domain, which removes is_associated_with::ubiquitin from ubiquitylated substrates: residues 1-240, with an active site comprising the is_associated_with::Cysteine91, is_associated_with::Alanine95, and is_associated_with::Glycine178 residues.
 * 2) a unique linker region, which includes a is_associated_with::Host cell factor C1 binding domain at residues 356-385.
 * 3) a is_associated_with::C-terminal domain: residues 598-729, which includes a UCH37-like domain (ULD) at residues 675-693 and two is_associated_with::Nuclear localization sequences at residues 656-661 and 717-722.

Function
In both is_associated_with::Drosophila and humans, BAP1 functions as the catalytic subunit of the Polycomb repressive deubiquitinase (PR-DUB) complex, which controls is_associated_with::homeobox genes by regulating the amount of ubiquitinated is_associated_with::Histone H2A in is_associated_with::Nucleosomes bound to their promoters. In flies and humans, the PR-DUB complex is formed through the interaction of BAP1 and is_associated_with::ASXL1 (Asx in fruit flies) BAP1 has also been shown to associate with other factors involved in chromatin modulation and transcriptional regulation, such as is_associated_with::Host cell factor C1,   which acts as an adaptor to couple is_associated_with::E2F transcription factors to is_associated_with::chromatin-modifying complexes during is_associated_with::cell cycle progression.

Role in disease
In cancer, BAP1 can function both as a is_associated_with::Tumor suppressor and as a is_associated_with::Metastasis suppressor.

Somatic mutations in cancer

 * BAP1 is_associated_with::somatic mutations were identified in a small number of breast and lung cancer cell lines, but BAP1 was first shown to act as a is_associated_with::tumor suppressor in cultured cells, where its deubiquitinase (UCH) domain and is_associated_with::Nuclear localization sequences were required for BAP1 to suppress cell growth.
 * In 2010, is_associated_with::Exome sequencing identified inactivating mutations in BAP1 in 47% of is_associated_with::Uveal melanomas, and BAP1 mutation was strongly associated with is_associated_with::metastasis. These is_associated_with::mutations included multiple is_associated_with::Nonsense mutations and splice site mutations throughout the gene.  is_associated_with::missense mutations were only found within the UCH and ULD domains, further supporting the requirement for BAP1 catalytic function.  This study also identified a is_associated_with::Germline mutation in one of the is_associated_with::uveal melanoma patients, suggesting that, besides being a is_associated_with::Metastasis suppressor, BAP1 could predispose certain people to more aggressive is_associated_with::uveal melanoma tumors.
 * BAP1 mutations have been identified in aggressive is_associated_with::Mesotheliomas with similar mutations as seen in melanomas,.
 * 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..

BAP1 tumor predisposition syndrome
Two studies used is_associated_with::Genome sequencing independently to identify is_associated_with::Germline mutations in BAP1 in families with is_associated_with::genetic predispositions to is_associated_with::mesothelioma and melanocytic skin tumors 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. Further studies have identified germline BAP1 mutations associated with other cancers. These studies suggest that is_associated_with::germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers.

Immunochemistry
is_associated_with::Immunohistochemistry for BAP1 is a prognostic biomarker to predict poor oncologic outcomes and adverse clinicopathological features in patients with non-metastatic is_associated_with::clear cell renal cell carcinoma (CCRCC). BAP1 assessment using immunohistochemistry on is_associated_with::needle biopsy may benefit preoperative risk stratification and guide treatment planning.

Interactions
BAP1 has been shown to interact with


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

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