The BRCA1 Breast Cancer Suppressor: Regulation of Transport, Dynamics, and Function at Multiple Subcellular Locations
Figure 3
Models for the hierarchical assembly and subsequent dynamics of the BRCA1-A DNA repair complex at foci. (a) A summary of recent understanding of the initial stages of BRCA1 recruitment to DNA damage foci (i.e., complexes formed at DNA double-strand breaks induced by IR). Upstream events include roles of ATM, MDC1, and RNF8 leading to RNF168/Ubc13-mediated ubiquitination of chromatin break-point components such as phospho-H2AX histones. This tagging of DNA breaks through the accumulation of Lys-63 ubiquitin (Ub, red) moieties leads to recruitment of RAP80 (green) via its ubiquitin-binding domain (dark green). RAP80 then recruits Abraxas/CCDC98 (orange) which in turn binds BRCA1 (grey), BARD1 (blue), BRCC36 (violet), and some additional components. This diagram exemplifies the “static” model for BRCA1 recruitment to foci shown in many previous review articles. (b) A new model for BRCA1-positive foci emphasizes the fact that most components undergo changes in their internal protein-protein interactions as the focal complex develops, such that once formed even the upstream RAP80 protein, previously thought to anchor the complex, is no longer required for BRCA1/BARD1 foci targeting (discussed in Section 5). In fact, at such mature foci, most components exchange rapidly at the focal complex, with RAP80 being one of the most dynamic components. The dynamic organisation of the BRCA1-A complex at foci has been proposed to comprise a small (~20% of total protein pools) immobilized fraction of each protein that forms an open scaffold, at which the dominant and dynamic pool (80%) transiently associates through rapid exchange [76].
