| Structural highlights
Disease
BAP1_HUMAN Pleural mesothelioma;Non-specific syndromic intellectual disability;Meningioma;BAP1-related tumor predisposition syndrome;Uveal melanoma;Familial melanoma. The gene represented in this entry is involved in disease pathogenesis. The disease is caused by variants affecting the gene represented in this entry. Disease susceptibility is associated with variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.
Function
BAP1_HUMAN Deubiquitinating enzyme that plays a key role in chromatin by mediating deubiquitination of histone H2A and HCFC1 (PubMed:12485996, PubMed:18757409, PubMed:20436459, PubMed:25451922, PubMed:35051358). Catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1) (PubMed:20436459, PubMed:25451922, PubMed:35051358). Does not deubiquitinate monoubiquitinated histone H2B (PubMed:20436459). Acts as a regulator of cell growth by mediating deubiquitination of HCFC1 N-terminal and C-terminal chains, with some specificity toward 'Lys-48'-linked polyubiquitin chains compared to 'Lys-63'-linked polyubiquitin chains (PubMed:19188440, PubMed:19815555). Deubiquitination of HCFC1 does not lead to increase stability of HCFC1 (PubMed:19188440, PubMed:19815555). Interferes with the BRCA1 and BARD1 heterodimer activity by inhibiting their ability to mediate ubiquitination and autoubiquitination (PubMed:19117993). It however does not mediate deubiquitination of BRCA1 and BARD1 (PubMed:19117993). Able to mediate autodeubiquitination via intramolecular interactions to couteract monoubiquitination at the nuclear localization signal (NLS), thereby protecting it from cytoplasmic sequestration (PubMed:24703950). Acts as a tumor suppressor (PubMed:9528852).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
References
- ↑ Mallery DL, Vandenberg CJ, Hiom K. Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. EMBO J. 2002 Dec 16;21(24):6755-62. PMID:12485996 doi:10.1093/emboj/cdf691
- ↑ Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, Wilkinson KD. BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Res. 2008 Sep 1;68(17):6953-62. PMID:18757409 doi:10.1158/0008-5472.CAN-08-0365
- ↑ Nishikawa H, Wu W, Koike A, Kojima R, Gomi H, Fukuda M, Ohta T. BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity. Cancer Res. 2009 Jan 1;69(1):111-9. PMID:19117993 doi:10.1158/0008-5472.CAN-08-3355
- ↑ Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M, Lee J, Liu J, O'Rourke K, Dixit VM, Wilson AC. Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol Cell Biol. 2009 Apr;29(8):2181-92. PMID:19188440 doi:10.1128/MCB.01517-08
- ↑ Machida YJ, Machida Y, Vashisht AA, Wohlschlegel JA, Dutta A. The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. J Biol Chem. 2009 Dec 4;284(49):34179-88. PMID:19815555 doi:10.1074/jbc.M109.046755
- ↑ Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, Wilm M, Muir TW, Muller J. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature. 2010 May 13;465(7295):243-7. doi: 10.1038/nature08966. Epub 2010 May 2. PMID:20436459 doi:https://dx.doi.org/10.1038/nature08966
- ↑ Mashtalir N, Daou S, Barbour H, Sen NN, Gagnon J, Hammond-Martel I, Dar HH, Therrien M, Affar el B. Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O. Mol Cell. 2014 May 8;54(3):392-406. doi: 10.1016/j.molcel.2014.03.002. Epub 2014 , Apr 3. PMID:24703950 doi:https://dx.doi.org/10.1016/j.molcel.2014.03.002
- ↑ Okino Y, Machida Y, Frankland-Searby S, Machida YJ. BRCA1-associated protein 1 (BAP1) deubiquitinase antagonizes the ubiquitin-mediated activation of FoxK2 target genes. J Biol Chem. 2015 Jan 16;290(3):1580-91. PMID:25451922 doi:10.1074/jbc.M114.609834
- ↑ Küry S, Ebstein F, Mollé A, Besnard T, Lee MK, Vignard V, Hery T, Nizon M, Mancini GMS, Giltay JC, Cogné B, McWalter K, Deb W, Mor-Shaked H, Li H, Schnur RE, Wentzensen IM, Denommé-Pichon AS, Fourgeux C, Verheijen FW, Faurie E, Schot R, Stevens CA, Smits DJ, Barr E, Sheffer R, Bernstein JA, Stimach CL, Kovitch E, Shashi V, Schoch K, Smith W, van Jaarsveld RH, Hurst ACE, Smith K, Baugh EH, Bohm SG, Vyhnálková E, Ryba L, Delnatte C, Neira J, Bonneau D, Toutain A, Rosenfeld JA, Audebert-Bellanger S, Gilbert-Dussardier B, Odent S, Laumonnier F, Berger SI, Smith ACM, Bourdeaut F, Stern MH, Redon R, Krüger E, Margueron R, Bézieau S, Poschmann J, Isidor B. Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder. Am J Hum Genet. 2022 Feb 3;109(2):361-372. PMID:35051358 doi:10.1016/j.ajhg.2021.12.011
- ↑ Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, Ishov AM, Tommerup N, Vissing H, Sekido Y, Minna J, Borodovsky A, Schultz DC, Wilkinson KD, Maul GG, Barlev N, Berger SL, Prendergast GC, Rauscher FJ 3rd. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene. 1998 Mar 5;16(9):1097-112. PMID:9528852 doi:10.1038/sj.onc.1201861
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