BAP1

Last updated
BAP1
Identifiers
Aliases BAP1 , HUCEP-13, UCHL2, hucep-6, BRCA1 associated protein 1, KURIS
External IDs OMIM: 603089 MGI: 1206586 HomoloGene: 3421 GeneCards: BAP1
Orthologs
SpeciesHumanMouse
Entrez

8314

104416

Ensembl

ENSG00000163930

ENSMUSG00000021901

UniProt

Q92560

Q99PU7

RefSeq (mRNA)

NM_004656

NM_027088

RefSeq (protein)

NP_004647

NP_081364

Location (UCSC) Chr 3: 52.4 – 52.41 Mb Chr 14: 30.97 – 30.98 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) is a deubiquitinating enzyme that in humans is encoded by the BAP1 gene. [5] [6] BAP1 encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its deubiquitinase activity. [5] 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. [7]

Contents

Nomenclature

BAP1 is also known as:

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) [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 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

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. [21]

Interactions

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. [22] Male and female animals underwent a standardized phenotypic screen [23] to determine the effects of deletion. [24] [25] [26] [27] Additional screens performed: - In-depth immunological phenotyping [28] - in-depth bone and cartilage phenotyping [29]

Related Research Articles

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<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

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<span class="mw-page-title-main">BRCA1</span> Gene known for its role in breast cancer

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<span class="mw-page-title-main">Ubiquitin carboxy-terminal hydrolase L1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxy-terminal hydrolase L1 is a deubiquitinating enzyme.

<span class="mw-page-title-main">Deubiquitinating enzyme</span>

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<span class="mw-page-title-main">MSH6</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">CHEK2</span> Protein-coding gene in humans

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<span class="mw-page-title-main">CDKN2A</span> Protein-coding gene in the species Homo sapiens

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References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021901 - Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  7. ↑ 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.
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  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
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  21. ↑ 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.
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  23. 1 2 "International Mouse Phenotyping Consortium".
  24. ↑ 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.
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  28. 1 2 "Infection and Immunity Immunophenotyping (3i) Consortium".
  29. ↑ "OBCD Consortium".

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