BioPAX pathway converted from "BRCA1:BARD1 heterodimer autoubiquitinates" in the Reactome database. LEFT-TO-RIGHT 6.3.2.19 BRCA1:BARD1 heterodimer autoubiquitinates This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> BRCA1:BARD1 Reactome DB_ID: 10105772 nucleoplasm GENE ONTOLOGY GO:0005654 BARD1 F1P8X2 Reactome DB_ID: 10105770 UniProt:F1P8X2 Canis familiaris NCBI Taxonomy 9615 UniProt F1P8X2 1 EQUAL 777 EQUAL Reactome Database ID Release 82 10105770 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10105770 Reactome R-CFA-5659775 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-5659775.1 Reactome http://www.reactome.org 1 BRCA1 A0A5F4C5E6 Reactome DB_ID: 10094613 UniProt:A0A5F4C5E6 UniProt A0A5F4C5E6 1 EQUAL 1863 EQUAL Reactome Database ID Release 82 10094613 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10094613 Reactome R-CFA-50949 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-50949.1 1 Reactome Database ID Release 82 10105772 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10105772 Reactome R-CFA-5659802 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-5659802.1 Converted from EntitySet in Reactome K6-Ub Reactome DB_ID: 10109262 A0A5F4C972 Ub-6-RPS27A(1-76) Reactome DB_ID: 10109234 UniProt:A0A5F4C972 UniProt A0A5F4C972 6 EQUAL ubiquitinylated lysine MOD MOD:01148 1 EQUAL 76 EQUAL Reactome Database ID Release 82 10109234 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109234 Reactome R-CFA-6782608 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-6782608.1 F1PEZ4 Ub-6-UBA52(1-76) Reactome DB_ID: 10109236 UniProt:F1PEZ4 UniProt F1PEZ4 6 EQUAL 1 EQUAL 76 EQUAL Reactome Database ID Release 82 10109236 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109236 Reactome R-CFA-6782616 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-6782616.1 F1PDG4 Ub-6-UBB(1-76) Reactome DB_ID: 10109238 UniProt:F1PDG4 UniProt F1PDG4 6 EQUAL 1 EQUAL 76 EQUAL Reactome Database ID Release 82 10109238 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109238 Reactome R-CFA-6782600 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-6782600.1 F1PDG4 Ub-82-UBB(77-152) Reactome DB_ID: 10109240 82 EQUAL 77 EQUAL 152 EQUAL Reactome Database ID Release 82 10109240 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109240 Reactome R-CFA-6782683 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-6782683.1 F1PDG4 Ub-158-UBB(153-228) Reactome DB_ID: 10109242 158 EQUAL 153 EQUAL 228 EQUAL Reactome Database ID Release 82 10109242 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109242 Reactome R-CFA-6782639 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-6782639.1 UBA52 Ub-6-UBC(1-76) P63050 Reactome DB_ID: 10109244 UniProt:P63050 UBA52 UniProt P63050 6 EQUAL 1 EQUAL 76 EQUAL Reactome Database ID Release 82 10109244 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109244 Reactome R-CFA-6782611 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-6782611.1 Reactome Database ID Release 82 10109262 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109262 Reactome R-CFA-6782648 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-6782648.1 6 K6PolyUb-BRCA1:K6PolyUb-BARD1 Reactome DB_ID: 10107737 F1P8X2 K6PolyUb-BARD1 Reactome DB_ID: 10107733 1 EQUAL 777 EQUAL Reactome Database ID Release 82 10107733 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10107733 Reactome R-CFA-9701024 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-9701024.1 1 A0A5F4C5E6 K6PolyUb-BRCA1 Reactome DB_ID: 10107735 1 EQUAL 1863 EQUAL Reactome Database ID Release 82 10107735 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10107735 Reactome R-CFA-9701022 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-9701022.1 1 Reactome Database ID Release 82 10107737 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10107737 Reactome R-CFA-9701028 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-9701028.1 ACTIVATION activeUnit: #Protein2 GENE ONTOLOGY GO:0004842 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 82 10134261 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10134261 Reactome Database ID Release 82 10134263 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10134263 Reactome R-CFA-9701000 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-9701000.1 In vivo, most BRCA1 and BARD1 polypeptides exist in the form of the BRCA1:BARD1 heterodimer. Although BRCA1 and BARD1 each harbor a RING domain (Miki et al. 1994; Wu et al. 1996), only the RING domain of BRCA1 is known to associate functionally with E2 ubiquitin conjugating enzymes (Brzovic et al. 2001). In vitro, BRCA1 alone exhibits a residual E3 ligase activity that is dramatically enhanced upon heterodimerization with BARD1 (Hashizume et al. 2001, Chen et al. 2002, Mallery et al. 2002, Wu-Baer et al. 2003, Xia et al. 2003). In addition to extensive auto-polyubiquitination on multiple unidentified lysine residues of both BRCA1 and BARD1, the heterodimer also mono- and/or poly-ubiquitinates a number of other substrates, including the H2A histones (Ohta et al. 2011, Kalb et al. 2014). Depending on the associated E2 conjugase, BRCA1:BARD1 can generate polyubiquitin chains of various linkages, including K6-linked ubiquitin polymers, that are not typically involved in proteasomal degradation (Wu-Baer et al. 2003, Nishikawa et al. 2004, Christensen et al. 2007). Autoubiquitination has been reported to increase the enzymatic activity of the BRCA1:BARD1 complex and may promote DNA damage response signaling (Mallery et al. 2002). In contrast, its E3 ligase activity can be suppressed by association with regulatory factors such as the BAP1 ubiquitin hydrolase (Nishikawa et al. 2009) or the UBXN1 ubiquitin-binding protein (Wu-Baer et al. 2010). The cancer-predisposing BRCA1 missense mutation C61G prevents binding to BARD1 and thereby impairs the ubiquitin ligase activity of BRCA1 (Wu et al. 1996, Ransburgh et al. 2010, Brzovic et al. 2001, Mallery et al. 2002, Wu-Baer et al. 2003). Studies in mouse cells have shown that the ubiquitin ligase activity of BRCA1 is not essential for its role in tumor suppression (Shakya et al. 2011) or double-strand DNA break repair by homologous recombination. 14638690 Pubmed 2004 Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase Nishikawa, Hiroyuki Ooka, Seido Sato, Ko Arima, Kei Okamoto, Joji Klevit, Rachel E Fukuda, Mamoru Ohta, Tomohiko J Biol Chem 279:3916-24 22034435 Pubmed 2011 BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity Shakya, Reena Reid, Latarsha J Reczek, Colleen R Cole, Francesca Egli, Dieter Lin, Chyuan-Sheng deRooij, Dirk G Hirsch, Steffen Ravi, Kandasamy Hicks, James B Szabolcs, Matthias Jasin, Maria Baer, Richard Ludwig, Thomas Science 334:525-8 20103620 Pubmed 2010 Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination Ransburgh, Derek J R Chiba, Natsuko Ishioka, Chikashi Toland, Amanda Ewart Parvin, Jeffrey D Cancer Res. 70:988-95 12485996 Pubmed 2002 Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains Mallery, Donna L Vandenberg, Cassandra J Hiom, Kevin EMBO J. 21:6755-62 11927591 Pubmed 2002 Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase Chen, Angus Kleiman, Frida E Manley, James L Ouchi, Toru Pan, Zhen-Qiang J. Biol. Chem. 277:22085-92 11526114 Pubmed 2001 BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein-protein interactions Brzovic, P S Meza, J E King, M C Klevit, R E J. Biol. Chem. 276:41399-406 19088202 Pubmed 2008 E3 ligase activity of BRCA1 is not essential for mammalian cell viability or homology-directed repair of double-strand DNA breaks Reid, Latarsha J Shakya, Reena Modi, Ami P Lokshin, Maria Cheng, Jiin-Tsuey Jasin, Maria Baer, Richard J Ludwig, Thomas Proc. Natl. Acad. Sci. U.S.A. 105:20876-81 12890688 Pubmed 2003 The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin Wu-Baer, Foon Lagrazon, Karen Yuan, Wei Baer, Richard J J. Biol. Chem. 278:34743-6 12431996 Pubmed 2003 Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein Xia, Yan Pao, Gerald M Chen, Hong-Wu Verma, Inder M Hunter, Tony J. Biol. Chem. 278:5255-63 17873885 Pubmed 2007 E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages Christensen, Devin E Brzovic, Peter S Klevit, Rachel E Nat. Struct. Mol. Biol. 14:941-8 20351172 Pubmed 2010 The UBXN1 protein associates with autoubiquitinated forms of the BRCA1 tumor suppressor and inhibits its enzymatic function Wu-Baer, Foon Ludwig, Thomas Baer, Richard Mol Cell Biol 30:2787-98 11278247 Pubmed 2001 The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation Hashizume, R Fukuda, M Maeda, I Nishikawa, H Oyake, D Yabuki, Y Ogata, H Ohta, T J Biol Chem 276:14537-40 25131202 Pubmed 2014 BRCA1 is a histone-H2A-specific ubiquitin ligase Kalb, Reinhard Mallery, Donna L Larkin, Conor Huang, Jeffrey T J Hiom, Kevin Cell Rep 8:999-1005 8944023 Pubmed 1996 Identification of a RING protein that can interact in vivo with the BRCA1 gene product Wu, L C Wang, Z W Tsan, J T Spillman, M A Phung, A Xu, X L Yang, M C Hwang, L Y Bowcock, A M Baer, R Nat. Genet. 14:430-40 21570976 Pubmed 2011 The BRCA1 ubiquitin ligase and homologous recombination repair Ohta, Tomohiko Sato, Ko Wu, Wenwen FEBS Lett 585:2836-44 inferred from electronic annotation EVIDENCE CODE ECO:0000203 INHIBITION Reactome Database ID Release 82 10134264 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10134264 BAP1:BARD1 Reactome DB_ID: 10109188 1 BAP1 E2R3W8 Reactome DB_ID: 10109158 UniProt:E2R3W8 UniProt E2R3W8 1 EQUAL 729 EQUAL Reactome Database ID Release 82 10109158 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109158 Reactome R-CFA-5689665 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-5689665.1 1 Reactome Database ID Release 82 10109188 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10109188 Reactome R-CFA-5690771 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CFA-5690771.1