BRCA1:BARD1 heterodimer autoubiquitinates

Stable Identifier
Reaction [transition]
Homo sapiens
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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.
Literature References
PubMed ID Title Journal Year
12485996 Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains

Vandenberg, CJ, Hiom, K, Mallery, DL

EMBO J. 2002
11927591 Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase

Pan, ZQ, Manley, JL, Kleiman, FE, Chen, A, Ouchi, T

J. Biol. Chem. 2002
12890688 The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin

Baer, RJ, Wu-Baer, F, Yuan, W, Lagrazon, K

J. Biol. Chem. 2003
Catalyst Activity

ubiquitin-protein transferase activity of BRCA1:BARD1 [nucleoplasm]

This event is regulated
Negatively by
Orthologous Events
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