BAP1_HUMAN
ID BAP1_HUMAN Reviewed; 729 AA.
AC Q92560; A8K993; Q6LEM0; Q7Z5E8;
DT 05-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 2.
DT 03-AUG-2022, entry version 177.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase BAP1 {ECO:0000305};
DE EC=3.4.19.12 {ECO:0000269|PubMed:20436459, ECO:0000269|PubMed:9528852};
DE AltName: Full=BRCA1-associated protein 1 {ECO:0000303|PubMed:9528852};
DE AltName: Full=Cerebral protein 6 {ECO:0000303|Ref.2};
GN Name=BAP1 {ECO:0000303|PubMed:9528852, ECO:0000312|HGNC:HGNC:950};
GN Synonyms=KIAA0272 {ECO:0000303|PubMed:9039502};
GN ORFNames=hucep-6 {ECO:0000303|Ref.2};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], ENZYME ACTIVITY, FUNCTION, MUTAGENESIS OF
RP CYS-91 AND LEU-691, INTERACTION WITH BRCA1, TISSUE SPECIFICITY, AND
RP SUBCELLULAR LOCATION.
RC TISSUE=B-cell;
RX PubMed=9528852; DOI=10.1038/sj.onc.1201861;
RA Jensen D.E., Proctor M., Marquis S.T., Gardner H.P., Ha S.I., Chodosh L.A.,
RA Ishov A.M., Tommerup N., Vissing H., Sekido Y., Minna J., Borodovsky A.,
RA Schultz D.C., Wilkinson K.D., Maul G.G., Barlev N., Berger S.,
RA Prendergast G.C., Rauscher F.J. III;
RT "BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and
RT enhances BRCA1-mediated cell growth suppression.";
RL Oncogene 16:1097-1112(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RA Yoshimoto M., Yazaki M., Takayama K., Matsumoto K.;
RT "Biological functions of a novel human gene, hucep-6, which is specifically
RT expressed in the central nervous system.";
RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=9039502; DOI=10.1093/dnares/3.5.321;
RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O.,
RA Tanaka A., Kotani H., Miyajima N., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. VI. The
RT coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of
RT cDNA clones from cell line KG-1 and brain.";
RL DNA Res. 3:321-329(1996).
RN [4]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 164-729.
RC TISSUE=Medulloblastoma;
RX PubMed=12800201; DOI=10.1002/ijc.11208;
RA Behrends U., Schneider I., Roessler S., Frauenknecht H., Golbeck A.,
RA Lechner B., Eigenstetter G., Zobywalski C., Mueller-Weihrich S.,
RA Graubner U., Schmid I., Sackerer D., Spaeth M., Goetz C., Prantl F.,
RA Asmuss H.-P., Bise K., Mautner J.;
RT "Novel tumor antigens identified by autologous antibody screening of
RT childhood medulloblastoma cDNA libraries.";
RL Int. J. Cancer 106:244-251(2003).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
RT phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [13]
RP INVOLVEMENT IN MESOM, AND VARIANTS CYS-63; VAL-81; TRP-91; ASP-95; ALA-315
RP AND VAL-685.
RX PubMed=21642991; DOI=10.1038/ng.855;
RA Bott M., Brevet M., Taylor B.S., Shimizu S., Ito T., Wang L., Creaney J.,
RA Lake R.A., Zakowski M.F., Reva B., Sander C., Delsite R., Powell S.,
RA Zhou Q., Shen R., Olshen A., Rusch V., Ladanyi M.;
RT "The nuclear deubiquitinase BAP1 is commonly inactivated by somatic
RT mutations and 3p21.1 losses in malignant pleural mesothelioma.";
RL Nat. Genet. 43:668-672(2011).
RN [14]
RP INVOLVEMENT IN TPDS.
RX PubMed=21874003; DOI=10.1038/ng.910;
RA Wiesner T., Obenauf A.C., Murali R., Fried I., Griewank K.G., Ulz P.,
RA Windpassinger C., Wackernagel W., Loy S., Wolf I., Viale A., Lash A.E.,
RA Pirun M., Socci N.D., Rutten A., Palmedo G., Abramson D., Offit K., Ott A.,
RA Becker J.C., Cerroni L., Kutzner H., Bastian B.C., Speicher M.R.;
RT "Germline mutations in BAP1 predispose to melanocytic tumors.";
RL Nat. Genet. 43:1018-1021(2011).
RN [15]
RP INVOLVEMENT IN TPDS AND MESOM.
RX PubMed=21874000; DOI=10.1038/ng.912;
RA Testa J.R., Cheung M., Pei J., Below J.E., Tan Y., Sementino E., Cox N.J.,
RA Dogan A.U., Pass H.I., Trusa S., Hesdorffer M., Nasu M., Powers A.,
RA Rivera Z., Comertpay S., Tanji M., Gaudino G., Yang H., Carbone M.;
RT "Germline BAP1 mutations predispose to malignant mesothelioma.";
RL Nat. Genet. 43:1022-1025(2011).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-292; SER-369; SER-521;
RP SER-537; SER-585 AND SER-597, AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [18]
RP VARIANTS ASP-95 AND VAL-178.
RX PubMed=10546591; DOI=10.1016/s0304-3835(99)90004-6;
RA Jensen D.E., Rauscher F.J. III;
RT "Defining biochemical functions for the BRCA1 tumor suppressor protein:
RT analysis of the BRCA1 binding protein BAP1.";
RL Cancer Lett. 143:S13-S17(1999).
RN [19]
RP FUNCTION.
RX PubMed=12485996; DOI=10.1093/emboj/cdf691;
RA Mallery D.L., Vandenberg C.J., Hiom K.;
RT "Activation of the E3 ligase function of the BRCA1/BARD1 complex by
RT polyubiquitin chains.";
RL EMBO J. 21:6755-6762(2002).
RN [20]
RP FUNCTION, SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, MUTAGENESIS OF
RP CYS-91; 656-LYS--ARG-661 AND 717-ARG--ARG-722, AND CHARACTERIZATION OF
RP VARIANTS ASP-95 AND VAL-178.
RX PubMed=18757409; DOI=10.1158/0008-5472.can-08-0365;
RA Ventii K.H., Devi N.S., Friedrich K.L., Chernova T.A., Tighiouart M.,
RA Van Meir E.G., Wilkinson K.D.;
RT "BRCA1-associated protein-1 is a tumor suppressor that requires
RT deubiquitinating activity and nuclear localization.";
RL Cancer Res. 68:6953-6962(2008).
RN [21]
RP FUNCTION, INTERACTION WITH BARD1 AND BRCA1, AND MUTAGENESIS OF CYS-91.
RX PubMed=19117993; DOI=10.1158/0008-5472.can-08-3355;
RA Nishikawa H., Wu W., Koike A., Kojima R., Gomi H., Fukuda M., Ohta T.;
RT "BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer
RT activity.";
RL Cancer Res. 69:111-119(2009).
RN [22]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH HCFC1, AND MUTAGENESIS OF
RP CYS-91 AND 363-ASN--TYR-366.
RX PubMed=19815555; DOI=10.1074/jbc.m109.046755;
RA Machida Y.J., Machida Y., Vashisht A.A., Wohlschlegel J.A., Dutta A.;
RT "The deubiquitinating enzyme BAP1 regulates cell growth via interaction
RT with HCF-1.";
RL J. Biol. Chem. 284:34179-34188(2009).
RN [23]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH HCFC1, AND MUTAGENESIS OF
RP CYS-91 AND 363-ASN--TYR-366.
RX PubMed=19188440; DOI=10.1128/mcb.01517-08;
RA Misaghi S., Ottosen S., Izrael-Tomasevic A., Arnott D., Lamkanfi M.,
RA Lee J., Liu J., O'Rourke K., Dixit V.M., Wilson A.C.;
RT "Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1
RT with cell cycle regulator host cell factor 1.";
RL Mol. Cell. Biol. 29:2181-2192(2009).
RN [24]
RP FUNCTION, CATALYTIC ACTIVITY, IDENTIFICATION IN THE PR-DUB COMPLEX, AND
RP INTERACTION WITH ASXL1.
RX PubMed=20436459; DOI=10.1038/nature08966;
RA Scheuermann J.C., de Ayala Alonso A.G., Oktaba K., Ly-Hartig N.,
RA McGinty R.K., Fraterman S., Wilm M., Muir T.W., Muller J.;
RT "Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-
RT DUB.";
RL Nature 465:243-247(2010).
RN [25]
RP FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION, NUCLEAR LOCALIZATION
RP SIGNAL, AND MUTAGENESIS OF 691-LEU--LYS-711.
RX PubMed=24703950; DOI=10.1016/j.molcel.2014.03.002;
RA Mashtalir N., Daou S., Barbour H., Sen N.N., Gagnon J., Hammond-Martel I.,
RA Dar H.H., Therrien M., Affar E.B.;
RT "Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic
RT sequestration mediated by the atypical ubiquitin ligase UBE2O.";
RL Mol. Cell 54:392-406(2014).
RN [26]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH FOXK2.
RX PubMed=24748658; DOI=10.1093/nar/gku274;
RA Ji Z., Mohammed H., Webber A., Ridsdale J., Han N., Carroll J.S.,
RA Sharrocks A.D.;
RT "The forkhead transcription factor FOXK2 acts as a chromatin targeting
RT factor for the BAP1-containing histone deubiquitinase complex.";
RL Nucleic Acids Res. 42:6232-6242(2014).
RN [27]
RP FUNCTION, INTERACTION WITH FOXK1 AND FOXK2, PHOSPHORYLATION AT THR-493, AND
RP MUTAGENESIS OF CYS-91; SER-489; SER-492; THR-493 AND THR-495.
RX PubMed=25451922; DOI=10.1074/jbc.m114.609834;
RA Okino Y., Machida Y., Frankland-Searby S., Machida Y.J.;
RT "BRCA1-associated protein 1 (BAP1) deubiquitinase antagonizes the
RT ubiquitin-mediated activation of FoxK2 target genes.";
RL J. Biol. Chem. 290:1580-1591(2015).
RN [28]
RP VARIANT PHE-47.
RX PubMed=25080371; DOI=10.1111/cge.12472;
RA de la Fouchardiere A., Cabaret O., Savin L., Combemale P., Schvartz H.,
RA Penet C., Bonadona V., Soufir N., Bressac-de Paillerets B.;
RT "Germline BAP1 mutations predispose also to multiple basal cell
RT carcinomas.";
RL Clin. Genet. 88:273-277(2015).
RN [29]
RP CHARACTERIZATION OF VARIANTS PHE-47; VAL-81; ASP-95 AND VAL-178.
RX PubMed=26680512; DOI=10.1038/srep18462;
RA Bhattacharya S., Hanpude P., Maiti T.K.;
RT "Cancer associated missense mutations in BAP1 catalytic domain induce
RT amyloidogenic aggregation: A new insight in enzymatic inactivation.";
RL Sci. Rep. 5:18462-18462(2015).
CC -!- FUNCTION: Deubiquitinating enzyme that plays a key role in chromatin by
CC mediating deubiquitination of histone H2A and HCFC1 (PubMed:12485996,
CC PubMed:18757409, PubMed:20436459, PubMed:25451922). Catalytic component
CC of the PR-DUB complex, a complex that specifically mediates
CC deubiquitination of histone H2A monoubiquitinated at 'Lys-119'
CC (H2AK119ub1) (PubMed:20436459, PubMed:25451922). Does not
CC deubiquitinate monoubiquitinated histone H2B (PubMed:20436459). Acts as
CC a regulator of cell growth by mediating deubiquitination of HCFC1 N-
CC terminal and C-terminal chains, with some specificity toward 'Lys-48'-
CC linked polyubiquitin chains compared to 'Lys-63'-linked polyubiquitin
CC chains (PubMed:19188440, PubMed:19815555). Deubiquitination of HCFC1
CC does not lead to increase stability of HCFC1 (PubMed:19188440,
CC PubMed:19815555). Interferes with the BRCA1 and BARD1 heterodimer
CC activity by inhibiting their ability to mediate ubiquitination and
CC autoubiquitination (PubMed:19117993). It however does not mediate
CC deubiquitination of BRCA1 and BARD1 (PubMed:19117993). Able to mediate
CC autodeubiquitination via intramolecular interactions to couteract
CC monoubiquitination at the nuclear localization signal (NLS), thereby
CC protecting it from cytoplasmic sequestration (PubMed:24703950). Acts as
CC a tumor suppressor (PubMed:9528852). {ECO:0000269|PubMed:12485996,
CC ECO:0000269|PubMed:18757409, ECO:0000269|PubMed:19117993,
CC ECO:0000269|PubMed:19188440, ECO:0000269|PubMed:19815555,
CC ECO:0000269|PubMed:20436459, ECO:0000269|PubMed:24703950,
CC ECO:0000269|PubMed:25451922, ECO:0000269|PubMed:9528852}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC residue protein attached to proteins as an intracellular targeting
CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:20436459,
CC ECO:0000269|PubMed:9528852};
CC -!- SUBUNIT: Component of the PR-DUB complex, at least composed of BAP1 and
CC ASXL1 (PubMed:20436459). Interacts with BRCA1 (via the RING finger)
CC (PubMed:19117993, PubMed:9528852). Interacts (via HBM-like motif) with
CC HCFC1 (PubMed:19188440, PubMed:19815555). Interacts (when
CC phosphorylated at Thr-493) with FOXK1 (PubMed:25451922). Interacts
CC (when phosphorylated at Thr-493) with FOXK2; leading to recruit the PR-
CC DUB complex and repress FOXK2 target genes (PubMed:24748658,
CC PubMed:25451922). {ECO:0000269|PubMed:19117993,
CC ECO:0000269|PubMed:19188440, ECO:0000269|PubMed:19815555,
CC ECO:0000269|PubMed:20436459, ECO:0000269|PubMed:24748658,
CC ECO:0000269|PubMed:25451922, ECO:0000269|PubMed:9528852}.
CC -!- INTERACTION:
CC Q92560; Q8IXJ9: ASXL1; NbExp=7; IntAct=EBI-1791447, EBI-1646500;
CC Q92560; P38398: BRCA1; NbExp=3; IntAct=EBI-1791447, EBI-349905;
CC Q92560; P38398-5: BRCA1; NbExp=2; IntAct=EBI-1791447, EBI-2015072;
CC Q92560; P51610: HCFC1; NbExp=4; IntAct=EBI-1791447, EBI-396176;
CC Q92560; Q14573: ITPR3; NbExp=12; IntAct=EBI-1791447, EBI-351055;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18757409,
CC ECO:0000269|PubMed:19188440, ECO:0000269|PubMed:19815555,
CC ECO:0000269|PubMed:24703950}. Nucleus {ECO:0000269|PubMed:18757409,
CC ECO:0000269|PubMed:19188440, ECO:0000269|PubMed:19815555,
CC ECO:0000269|PubMed:24703950, ECO:0000269|PubMed:24748658,
CC ECO:0000269|PubMed:9528852}. Note=Mainly nuclear. Binds to chromatin.
CC Localizes to the cytoplasm when monoubiquitinated by the E2/E3 hybrid
CC ubiquitin-protein ligase UBE2O (PubMed:24703950).
CC {ECO:0000269|PubMed:24703950}.
CC -!- TISSUE SPECIFICITY: Highly expressed in testis, placenta and ovary.
CC Expressed in breast. {ECO:0000269|PubMed:9528852}.
CC -!- PTM: Ubiquitinated: monoubiquitinated at multiple site of its nuclear
CC localization signal (NLS) BY UBE2O, leading to cytoplasmic retention.
CC Able to mediate autodeubiquitination via intramolecular interactions to
CC couteract cytoplasmic retention. {ECO:0000269|PubMed:24703950}.
CC -!- DISEASE: Mesothelioma, malignant (MESOM) [MIM:156240]: An aggressive
CC neoplasm of the serosal lining of the chest. It appears as broad sheets
CC of cells, with some regions containing spindle-shaped, sarcoma-like
CC cells and other regions showing adenomatous patterns. Pleural
CC mesotheliomas have been linked to exposure to asbestos.
CC {ECO:0000269|PubMed:21642991, ECO:0000269|PubMed:21874000}. Note=The
CC gene represented in this entry is involved in disease pathogenesis.
CC -!- DISEASE: Tumor predisposition syndrome (TPDS) [MIM:614327]: A condition
CC characterized by predisposition to develop a variety of tumors,
CC including benign melanocytic tumors as well as several malignant
CC tumors, including uveal melanoma, cutaneous melanoma, malignant
CC mesothelioma on exposure to asbestos, lung adenocarcinoma and
CC meningioma. {ECO:0000269|PubMed:21874000, ECO:0000269|PubMed:21874003}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- SIMILARITY: Belongs to the peptidase C12 family. BAP1 subfamily.
CC {ECO:0000305}.
CC -!- CAUTION: According to a report, interaction with FOXK2 is not dependent
CC on phosphorylation of BAP1 (PubMed:24748658). However, it was later
CC shown that phosphorylation at Thr-493 promotes interaction with FOXK2
CC (PubMed:25451922). {ECO:0000269|PubMed:24748658,
CC ECO:0000269|PubMed:25451922}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA13401.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/BAP1ID755ch3p21.html";
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DR EMBL; AF045581; AAC15970.1; -; mRNA.
DR EMBL; D88812; BAB46921.1; -; mRNA.
DR EMBL; D87462; BAA13401.2; ALT_INIT; mRNA.
DR EMBL; AK292608; BAF85297.1; -; mRNA.
DR EMBL; CH471055; EAW65220.1; -; Genomic_DNA.
DR EMBL; BC001596; AAH01596.1; -; mRNA.
DR EMBL; AY130008; AAN05092.1; -; mRNA.
DR CCDS; CCDS2853.1; -.
DR RefSeq; NP_004647.1; NM_004656.3.
DR AlphaFoldDB; Q92560; -.
DR SMR; Q92560; -.
DR BioGRID; 113911; 212.
DR ComplexPortal; CPX-414; PR-DUB complex.
DR DIP; DIP-47004N; -.
DR IntAct; Q92560; 83.
DR MINT; Q92560; -.
DR STRING; 9606.ENSP00000417132; -.
DR BindingDB; Q92560; -.
DR ChEMBL; CHEMBL1293314; -.
DR MEROPS; C12.004; -.
DR GlyGen; Q92560; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q92560; -.
DR MetOSite; Q92560; -.
DR PhosphoSitePlus; Q92560; -.
DR BioMuta; BAP1; -.
DR DMDM; 68565074; -.
DR EPD; Q92560; -.
DR jPOST; Q92560; -.
DR MassIVE; Q92560; -.
DR MaxQB; Q92560; -.
DR PaxDb; Q92560; -.
DR PeptideAtlas; Q92560; -.
DR PRIDE; Q92560; -.
DR ProteomicsDB; 75316; -.
DR Antibodypedia; 3812; 454 antibodies from 37 providers.
DR DNASU; 8314; -.
DR Ensembl; ENST00000460680.6; ENSP00000417132.1; ENSG00000163930.10.
DR GeneID; 8314; -.
DR KEGG; hsa:8314; -.
DR MANE-Select; ENST00000460680.6; ENSP00000417132.1; NM_004656.4; NP_004647.1.
DR UCSC; uc003ddx.5; human.
DR CTD; 8314; -.
DR DisGeNET; 8314; -.
DR GeneCards; BAP1; -.
DR GeneReviews; BAP1; -.
DR HGNC; HGNC:950; BAP1.
DR HPA; ENSG00000163930; Low tissue specificity.
DR MalaCards; BAP1; -.
DR MIM; 156240; phenotype.
DR MIM; 603089; gene.
DR MIM; 614327; phenotype.
DR neXtProt; NX_Q92560; -.
DR OpenTargets; ENSG00000163930; -.
DR Orphanet; 289539; BAP1-related tumor predisposition syndrome.
DR Orphanet; 618; Familial melanoma.
DR Orphanet; 2495; Meningioma.
DR Orphanet; 528084; Non-specific syndromic intellectual disability.
DR Orphanet; 50251; Pleural mesothelioma.
DR Orphanet; 39044; Uveal melanoma.
DR PharmGKB; PA25254; -.
DR VEuPathDB; HostDB:ENSG00000163930; -.
DR eggNOG; KOG2778; Eukaryota.
DR GeneTree; ENSGT00940000156388; -.
DR HOGENOM; CLU_018316_5_0_1; -.
DR InParanoid; Q92560; -.
DR OMA; VLKMNRQ; -.
DR OrthoDB; 1363547at2759; -.
DR PhylomeDB; Q92560; -.
DR TreeFam; TF313976; -.
DR BRENDA; 3.4.19.12; 2681.
DR PathwayCommons; Q92560; -.
DR Reactome; R-HSA-5689603; UCH proteinases.
DR Reactome; R-HSA-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR SignaLink; Q92560; -.
DR SIGNOR; Q92560; -.
DR BioGRID-ORCS; 8314; 459 hits in 1136 CRISPR screens.
DR ChiTaRS; BAP1; human.
DR GeneWiki; BAP1; -.
DR GenomeRNAi; 8314; -.
DR Pharos; Q92560; Tbio.
DR PRO; PR:Q92560; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q92560; protein.
DR Bgee; ENSG00000163930; Expressed in left testis and 162 other tissues.
DR ExpressionAtlas; Q92560; baseline and differential.
DR Genevisible; Q92560; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0035517; C:PR-DUB complex; IDA:UniProtKB.
DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
DR GO; GO:0031490; F:chromatin DNA binding; IEA:Ensembl.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0008233; F:peptidase activity; NAS:UniProtKB.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0035726; P:common myeloid progenitor cell proliferation; IEA:Ensembl.
DR GO; GO:0043249; P:erythrocyte maturation; IEA:Ensembl.
DR GO; GO:0010467; P:gene expression; IEA:Ensembl.
DR GO; GO:0061484; P:hematopoietic stem cell homeostasis; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0070661; P:leukocyte proliferation; IEA:Ensembl.
DR GO; GO:0061519; P:macrophage homeostasis; IEA:Ensembl.
DR GO; GO:0000278; P:mitotic cell cycle; IEA:Ensembl.
DR GO; GO:0035522; P:monoubiquitinated histone H2A deubiquitination; IDA:UniProtKB.
DR GO; GO:0035520; P:monoubiquitinated protein deubiquitination; IDA:UniProtKB.
DR GO; GO:0033028; P:myeloid cell apoptotic process; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0070050; P:neuron cellular homeostasis; IEA:Ensembl.
DR GO; GO:0030223; P:neutrophil differentiation; IEA:Ensembl.
DR GO; GO:0043363; P:nucleate erythrocyte differentiation; IEA:Ensembl.
DR GO; GO:0036344; P:platelet morphogenesis; IEA:Ensembl.
DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; HMP:ParkinsonsUK-UCL.
DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR GO; GO:0071108; P:protein K48-linked deubiquitination; IMP:UniProtKB.
DR GO; GO:0036211; P:protein modification process; NAS:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; IMP:UniProtKB.
DR GO; GO:0001558; P:regulation of cell growth; IMP:UniProtKB.
DR GO; GO:1900015; P:regulation of cytokine production involved in inflammatory response; IEA:Ensembl.
DR GO; GO:0050727; P:regulation of inflammatory response; IEA:Ensembl.
DR GO; GO:0010035; P:response to inorganic substance; IEA:Ensembl.
DR GO; GO:0002574; P:thrombocyte differentiation; IEA:Ensembl.
DR GO; GO:0001894; P:tissue homeostasis; IEA:Ensembl.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR Gene3D; 3.40.532.10; -; 1.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR001578; Peptidase_C12_UCH.
DR InterPro; IPR036959; Peptidase_C12_UCH_sf.
DR InterPro; IPR041507; UCH_C.
DR PANTHER; PTHR10589; PTHR10589; 1.
DR Pfam; PF01088; Peptidase_C12; 1.
DR Pfam; PF18031; UCH_C; 1.
DR PRINTS; PR00707; UBCTHYDRLASE.
DR SUPFAM; SSF54001; SSF54001; 1.
PE 1: Evidence at protein level;
KW Chromatin regulator; Coiled coil; Cytoplasm; Hydrolase; Nucleus;
KW Phosphoprotein; Protease; Reference proteome; Thiol protease;
KW Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1..729
FT /note="Ubiquitin carboxyl-terminal hydrolase BAP1"
FT /id="PRO_0000211069"
FT REGION 301..351
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 372..435
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 464..524
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 575..623
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 596..721
FT /note="Interaction with BRCA1"
FT REGION 703..729
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 630..661
FT /evidence="ECO:0000255"
FT MOTIF 363..366
FT /note="HBM-like motif"
FT /evidence="ECO:0000269|PubMed:19188440,
FT ECO:0000269|PubMed:19815555, ECO:0000269|PubMed:25451922"
FT MOTIF 717..722
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:18757409,
FT ECO:0000269|PubMed:24703950"
FT COMPBIAS 583..602
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 704..729
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 91
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:18757409,
FT ECO:0000269|PubMed:19117993, ECO:0000269|PubMed:19188440,
FT ECO:0000269|PubMed:19815555, ECO:0000269|PubMed:25451922,
FT ECO:0000269|PubMed:9528852"
FT ACT_SITE 169
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:P09936"
FT SITE 184
FT /note="Important for enzyme activity"
FT /evidence="ECO:0000250|UniProtKB:P09936"
FT MOD_RES 292
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 369
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 395
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q99PU7"
FT MOD_RES 493
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:25451922"
FT MOD_RES 521
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 537
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 585
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 597
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VARIANT 47
FT /note="I -> F (found in a primary uveal melanoma; somatic
FT mutation; induces cytoplasmic accumulation; loss of
FT deubiquitinase activity; up-regulates heat shock response;
FT induces formation of amyloid-beta aggregates)"
FT /evidence="ECO:0000269|PubMed:25080371,
FT ECO:0000269|PubMed:26680512"
FT /id="VAR_075251"
FT VARIANT 63
FT /note="S -> C (found in a malignant pleural mesothelioma
FT sample; somatic mutation; dbSNP:rs747311942)"
FT /evidence="ECO:0000269|PubMed:21642991"
FT /id="VAR_065976"
FT VARIANT 81
FT /note="F -> V (found in a malignant pleural mesothelioma
FT sample; somatic mutation; induces cytoplasmic accumulation;
FT loss of deubiquitinase activity; up-regulates heat shock
FT response; induces formation of amyloid-beta aggregates)"
FT /evidence="ECO:0000269|PubMed:21642991,
FT ECO:0000269|PubMed:26680512"
FT /id="VAR_065977"
FT VARIANT 91
FT /note="C -> W (found in a malignant pleural mesothelioma
FT sample)"
FT /evidence="ECO:0000269|PubMed:21642991"
FT /id="VAR_065978"
FT VARIANT 95
FT /note="A -> D (in a lung cancer sample; also found in a
FT malignant pleural mesothelioma cell line; induces
FT cytoplasmic accumulation; loss of deubiquitinase activity;
FT up-regulates heat shock response; induces formation of
FT amyloid-beta aggregates)"
FT /evidence="ECO:0000269|PubMed:10546591,
FT ECO:0000269|PubMed:18757409, ECO:0000269|PubMed:21642991,
FT ECO:0000269|PubMed:26680512"
FT /id="VAR_063498"
FT VARIANT 178
FT /note="G -> V (in a lung cancer sample; induces cytoplasmic
FT accumulation; impairs deubiquitinase activity; up-regulates
FT heat shock response; induces formation of beta-amyloid
FT aggregates)"
FT /evidence="ECO:0000269|PubMed:10546591,
FT ECO:0000269|PubMed:18757409, ECO:0000269|PubMed:26680512"
FT /id="VAR_063499"
FT VARIANT 315
FT /note="E -> A (found in a malignant pleural mesothelioma
FT sample; dbSNP:rs149974450)"
FT /evidence="ECO:0000269|PubMed:21642991"
FT /id="VAR_065979"
FT VARIANT 616
FT /note="V -> E (in dbSNP:rs35353781)"
FT /id="VAR_051517"
FT VARIANT 685
FT /note="E -> V (found in a malignant pleural mesothelioma
FT cell line)"
FT /evidence="ECO:0000269|PubMed:21642991"
FT /id="VAR_065980"
FT MUTAGEN 91
FT /note="C->A,S: Abolishes enzymatic activity without
FT affecting its ability to interfere with BRCA1 E3 ligase
FT activity. Does not affect interaction with FOXK1 and
FT FOXK2."
FT /evidence="ECO:0000269|PubMed:18757409,
FT ECO:0000269|PubMed:19117993, ECO:0000269|PubMed:19188440,
FT ECO:0000269|PubMed:19815555, ECO:0000269|PubMed:25451922,
FT ECO:0000269|PubMed:9528852"
FT MUTAGEN 363..366
FT /note="NHNY->AAAA: Abolishes interaction with HCFC1 without
FT affecting interaction with FOXK1 and FOXK2."
FT /evidence="ECO:0000269|PubMed:19188440,
FT ECO:0000269|PubMed:19815555, ECO:0000269|PubMed:25451922"
FT MUTAGEN 489
FT /note="S->A: Does not affect interaction with FOXK1 and
FT FOXK2."
FT /evidence="ECO:0000269|PubMed:25451922"
FT MUTAGEN 492
FT /note="S->A: Does not affect interaction with FOXK1 and
FT FOXK2."
FT /evidence="ECO:0000269|PubMed:25451922"
FT MUTAGEN 493
FT /note="T->A,L: Abolished interaction with FOXK1 and FOXK2."
FT /evidence="ECO:0000269|PubMed:25451922"
FT MUTAGEN 495
FT /note="T->A: Does not affect interaction with FOXK1 and
FT FOXK2."
FT /evidence="ECO:0000269|PubMed:25451922"
FT MUTAGEN 656..661
FT /note="KRKKFK->AAAAAA: Does not affect nuclear
FT localization."
FT /evidence="ECO:0000269|PubMed:18757409"
FT MUTAGEN 691..711
FT /note="Missing: Abolishes ubiquitination by UBE2O."
FT /evidence="ECO:0000269|PubMed:24703950"
FT MUTAGEN 691
FT /note="L->P: Abolishes interaction with BRCA1."
FT /evidence="ECO:0000269|PubMed:9528852"
FT MUTAGEN 717..722
FT /note="RRKRSR->AAAAAA: Abolishes nuclear localization."
FT /evidence="ECO:0000269|PubMed:18757409"
SQ SEQUENCE 729 AA; 80362 MW; 031DA03AE1841D85 CRC64;
MNKGWLELES DPGLFTLLVE DFGVKGVQVE EIYDLQSKCQ GPVYGFIFLF KWIEERRSRR
KVSTLVDDTS VIDDDIVNNM FFAHQLIPNS CATHALLSVL LNCSSVDLGP TLSRMKDFTK
GFSPESKGYA IGNAPELAKA HNSHARPEPR HLPEKQNGLS AVRTMEAFHF VSYVPITGRL
FELDGLKVYP IDHGPWGEDE EWTDKARRVI MERIGLATAG EPYHDIRFNL MAVVPDRRIK
YEARLHVLKV NRQTVLEALQ QLIRVTQPEL IQTHKSQESQ LPEESKSASN KSPLVLEANR
APAASEGNHT DGAEEAAGSC AQAPSHSPPN KPKLVVKPPG SSLNGVHPNP TPIVQRLPAF
LDNHNYAKSP MQEEEDLAAG VGRSRVPVRP PQQYSDDEDD YEDDEEDDVQ NTNSALRYKG
KGTGKPGALS GSADGQLSVL QPNTINVLAE KLKESQKDLS IPLSIKTSSG AGSPAVAVPT
HSQPSPTPSN ESTDTASEIG SAFNSPLRSP IRSANPTRPS SPVTSHISKV LFGEDDSLLR
VDCIRYNRAV RDLGPVISTG LLHLAEDGVL SPLALTEGGK GSSPSIRPIQ GSQGSSSPVE
KEVVEATDSR EKTGMVRPGE PLSGEKYSPK ELLALLKCVE AEIANYEACL KEEVEKRKKF
KIDDQRRTHN YDEFICTFIS MLAQEGMLAN LVEQNISVRR RQGVSIGRLH KQRKPDRRKR
SRPYKAKRQ
