BAP1
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| Location (UCSC) | Chr 3: 52.4 – 52.41 Mb | Chr 14: 30.97 – 30.98 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) is a
transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.[7]
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
domains
:
- 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.
- a unique linker region, which includes a bindingdomain at residues 356-385.
- a C-terminal domain: residues 598-729, which includes a UCH37-like domain (ULD) at residues 675-693 and two Nuclear localization sequencesat 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)[8][9] BAP1 has also been shown to associate with other factors involved in chromatin modulation and transcriptional regulation, such as Host cell factor C1,[10][11][12] 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 suppressor in cultured cells, where its deubiquitinase (UCH) domain and nuclear localization sequences were required for BAP1 to suppress cell growth.[13]
- In 2010, 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 melanomatumors.
- BAP1 mutations have been identified in aggressive mesotheliomas with similar mutations as seen in melanomas,.[15]
- 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.[16]
BAP1 tumor predisposition syndrome
Two studies used
genome sequencing independently to identify germline mutations in BAP1 in families with genetic predispositions to mesothelioma[17] and melanocytic skin tumors[18] 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.[19]
Further studies have identified germline BAP1 mutations associated with other cancers.[20] These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers.
Immunochemistry
needle biopsy may benefit preoperative risk stratification and guide treatment planning.[21]
Interactions
BAP1 has been shown to
interact
with
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000163930 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021901 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ S2CID 1019611.
- ^ "Entrez Gene: BAP1 BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)".
- PMID 17717194.
- ^ PMID 20436459.
- ^ PMID 19615732.
- ^ PMID 19815555.
- PMID 19188440.
- PMID 20805357.
- PMID 18757409.
- PMID 21051595.
- PMID 21642991.
- PMID 22683710.
- PMID 21874000.
- PMID 21874003.
- ^ 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.
- PMID 21941004.
- PMID 24076305.
External links
- Human BAP1 genome location and BAP1 gene details page in the UCSC Genome Browser.
Further reading
- Harbour JW (Mar 2012). "The genetics of uveal melanoma: an emerging framework for targeted therapy". Pigment Cell & Melanoma Research. 25 (2): 171–81. 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. 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. PMID 22038994.
- Goldstein AM (Oct 2011). "Germline BAP1 mutations and tumor susceptibility". Nature Genetics. 43 (10): 925–6. PMID 21956388.
- Materin MA, Faries M, Kluger HM (2011). "Molecular alternations in uveal melanoma". Current Problems in Cancer. 35 (4): 211–24. 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. PMID 21851340.
- Eletr ZM, Wilkinson KD (Jun 2011). "An emerging model for BAP1's role in regulating cell cycle progression". 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. 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. 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. 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. 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. PMID 10546591.