The RING Heterodimer BRCA1-BARD1 Is a Ubiquitin Ligase Inactivated by a Breast Cancer-derived Mutation*

By R. Hashizume, M. Fukuda, I. Maeda, Hiroyuki Nishikawa, Daisuke Oyake, Yukari Yabuki, H. Ogata, T. Ohta. Journal of Biological Chemistry, 2001

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BRCA1-BARD1 constitutes a heterodimeric RING finger complex associated through its N-terminal regions. Here we demonstrate that the BRCA1-BARD1 heterodimeric RING finger complex contains significant ubiquitin ligase activity that can be disrupted by a breast cancer-derived RING finger mutation in BRCA1. Whereas individually BRCA1 and BARD1 have very low ubiquitin ligase activities in vitro, BRCA1 combined with BARD1 exhibits dramatically higher activity. Bacterially purified RING finger domains comprising residues 1–304 of BRCA1 and residues 25–189 of BARD1 are capable of polymerizing ubiquitin. The steady-state level of transfected BRCA1 in vivo was increased by co-transfection of BARD1, and reciprocally that of transfected BARD1 was increased by BRCA1 in a dose-dependent manner. The breast cancer-derived BARD1-interaction-deficient mutant, BRCA1C61G, does not exhibit ubiquitin ligase activity in vitro. These results suggest that the BRCA1-BARD1 complex contains a ubiquitin ligase activity that is important in prevention of breast and ovarian cancer development.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e2cb818521ccc6287525fae130b40a7b511714b3

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Citations in the corpus

RING domain E3 ubiquitin ligases. (2009, background): “However, when assayed in conjunction with Brca1-Bard1, it synthesizes predominantly Lys6-linked chains (89, 90), and with the heterodimeric TRIAD subfamily E3 Hoil-1L-Rbck1/Hoip, it generates linear (i.e., linked together via the N terminus) ubiquitin chains (100).”
Massively Parallel Functional Analysis of BRCA1 RING Domain Variants (2015, background): “The BRCA1 RING domain heterodimerizes with the RING domain of BARD1 to comprise an E3 ubiquitin ligase (Hashizume et al. 2001).”
BRCA1 and BRCA2: 1994 and beyond (2004, background): “Disease-associated mutations in BARD1 , however, are rare in BRCA1 - and BRCA2 -negative breast tumour”
The General Transcription Machinery and General Cofactors (2006, background): “Together, BRCA1 and BARD1 form an active E3 ubiquitin ligase able to work in conjunction with the E2 ubiquitin-conjugating enzyme UbcH5c to promote substrate ubiquitination (Hashizume et al., 2001; Brzovic et al., 2003) and likely pol II degradation.”
The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability (2006, background): “The association between these two proteins is mediated through their respective RING domains, and together they exhibit E3 ubiquitin ligase activity, which can be disrupted by cancerpredisposing mutations within the RING domain of BRCA1 (Hashizume et al., 2001; Ruffner et al., 2001).”
Network modeling links breast cancer susceptibility and centrosome dysfunction. (2007, background): “, and HMMR-BRCA1 protein complexes are most prominent during G2/M, we examined the possibility that HMMR might be a substrate of the BRCA1-BARD1 E3 ubiquitin ligase activit”
IAPs, RINGs and ubiquitylation (2005, background): “Whereas UBCH5 binding to a heterodimer of BRCA1 and BARD1 activated the E3 ligase activity of this heterodimer, binding of the highly similar UBCH7 did not promote BRCA1– BARD1-mediated polyubiquitylatio”
Targeting the ubiquitin system in cancer therapy (2009, background): “Mutations in the BRCA1 locus that lead to the expression of a truncated or E3-inactive BRCA1 protein are strongly linked to the development of ovarian and breast cance”
Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. (2011, background): “BRCA1 and its interacting partner, BARD1 (BRCA1associated RING domain), comprise the first mammalian E3 enzyme shown to function within foci at sites of DNA breaks (Hashizume et al. 2001; Morris and Solomon 2004).”
Regulation of DNA repair throughout the cell cycle (2008, background): “BRCA1, which also associates with FANCJ, is a ubiquitin ligas”
Playing the end game: DNA double-strand break repair pathway choice. (2012, background): “It is intriguing that BRCA1 and its partner BARD1 heterodimerize via their RING domains to form an E3-ubiquitin (Ub) ligase (Hashizume et al., 2001).”
Ubiquitin: structures, functions, mechanisms. (2004, background): “This association is required for robust ligase activity [81] even though the BRCA1/BARD1 interface does not include a significant contribution from either RING domain [80].”