The BRCA1 Breast Cancer Suppressor: Regulation of Transport, Dynamics, and Function at Multiple Subcellular Locations
Figure 1
BRCA1 domain structure and subcellular transport pathways. (a) Protein domain structure of BRCA1 showing the location of nuclear localization signals (NLSs), nuclear export signals (NESs), and binding sites for BARD1 and gamma-tubulin. The RING and BRCT protein interaction domains are shown at the amino and carboxy termini, respectively. (b) Diagram summarizing the distribution and movement of BRCA1 in the cell. Once translated in the cytoplasm, BRCA1 can move to the centrosome where it dimerizes with BARD1 to ubiquitinate proteins such as gamma-tubulin that regulate centrosome duplication and microtubule nucleation, or to the mitochondria where it is implicated in cell survival and/or apoptosis regulation. BRCA1 enters the nucleus through the importin-alpha/beta pathway and locates at nuclear DNA replication sites. In response to DNA damage, BRCA1 is sequestered (as a dimer with BARD1) to different types of DNA repair complexes at foci. The interaction with BARD1 tends to trap BRCA1 in the nucleus through the masking of its NES. If BRCA1 is not bound to BARD1, it is exported to the cytoplasm by the CRM1 export receptor, and this has been linked to the roles of BRCA1 in apoptosis and in centrosome duplication as revealed by functional comparison of wild-type and NES-mutated forms of BRCA1.
