BRCA1:BARD1 heterodimer autoubiquitinates

Stable Identifier
R-HSA-9701000
Type
Reaction [transition]
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
General
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

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
11927591 Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase

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

J. Biol. Chem. 2002
12485996 Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains

Mallery, DL, Vandenberg, CJ, Hiom, K

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

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

J. Biol. Chem. 2003
Participants
Participates
Catalyst Activity

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

This event is regulated
Negatively by
Authored
Reviewed
Created
Cite Us!