BRCA1-dependent Ub-ligase activity

BRCA1 is a breast and ovarian cancer tumor suppressor protein that associates with BARD1 to form a RING/RING heterodimer. The BRCA1/BARD1 RING complex functions as an ubiquitin (Ub) ligase with activity substantially greater than individual BRCA1 or BARD1 subunits. The BRCA1 tumor suppressor forms a heterodimer with the BARD1 protein, and the resulting complex functions as an E3 ubiquitin ligase that catalyzes the synthesis of polyubiquitin chains. UbcH5c and UbcH7 also interact with the BRCA1/BARD1 complex with similar affinity (not shown on this figure). Although the in vivo substrate(s) is not yet known, BRCA1 has been observed to undergo autoubiquitination and is capable of monoubiquitinating histones 2A and 2AX in vitro

Contributor: Kosi Gramatikoff, PhD

REFERENCES: Ellen E et al.Loss of Bard1, the Heterodimeric Partner of the Brca1 Tumor Suppressor, Results in Early Embryonic Lethality and Chromosomal Instability Mol. Cell. Biol., Jul 2003; 23: 5056 - 5063. F. Wu-Baer et al. The BRCA1/BARD1 Heterodimer Assembles Polyubiquitin Chains through an Unconventional Linkage Involving Lysine Residue K6 of Ubiquitin J. Biol. Chem., September 12, 2003; 278(37): 34743 - 34746. P.-Y. Wu et al. A conserved catalytic residue in the ubiquitin-conjugating enzyme family EMBO J., October 1, 2003; 22(19): 5241 - 5250. Peter S. Brzovic et al. Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex PNAS, May 2003; 100: 5646 - 5651 Ulrica K. Westermark et al. BARD1 Participates with BRCA1 in Homology-Directed Repair of Chromosome Breaks Mol. Cell. Biol., Nov 2003; 23: 7926 - 7936.