Breast
cancer
Cancer Res.
2006 Feb 15;66(4):2012-8.
BRCA1 DNA-binding activity is stimulated
by BARD1.
Simons
AM, Horwitz AA, Starita LM, Griffin
K, Williams
RS, Glover
JN, Parvin JD.
Graduate Program in Biological and Biomedical Sciences,
The breast- and ovarian-specific tumor suppressor BRCA1 has been implicated
in numerous cellular processes, including transcription, ubiquitination, and DNA repair. Its tumor suppression
activity is tightly linked to that of BARD1, a protein that heterodimerizes with BRCA1. It has been previously
shown that BRCA1 binds to DNA, an interesting functional observation in
light of the genetic data linking BRCA1 to DNA repair pathways. In this
work, we reexamine the DNA-binding properties of BRCA1, comparing them with
the DNA-binding properties of the BRCA1/BARD1 heterodimer.
Because nuclear BRCA1 exists as a heterodimer
with BARD1, it is likely that in vitro studies of the heterodimer
will provide a more accurate model of physiologic conditions. Our results
indicate that whereas BARD1 cannot directly bind DNA, it does enhance DNA
binding by BRCA1. This is a surprising observation as both DNA-binding
domains are distal to the BARD1-interacting RING domain of BRCA1. Further
analysis of the dimerization reveals that the
BRCA1/BARD1 interaction is not limited to the amino-terminal RING domains
of each protein. The carboxyl terminus of BRCA1 contributes significantly
to the stability of the heterodimer. We also show
that the presence of BARD1 has a secondary effect, as autoubiquitination
of BRCA1/BARD1 heterodimers additionally enhances
the affinity of BRCA1 for DNA. Together, these data suggest that BRCA1 and
BARD1 heterodimerization is stabilized via
domains not previously thought to interact and that BARD1 acts in both ubiquitination-dependent and ubiquitination-independent
ways to influence the role of BRCA1 in DNA repair.
PMID: 16489000 [PubMed - indexed for MEDLINE]