Figure 7. Model of spatially differential Brca1 recruitment to the DSB.

The data presented herein support the following steps involved in Brca1 recruitment to chromatin and function after DNA breakage: 1) Following DSB induction, Brca1 interacts with Nbs1, resulting in recruitment of a small fraction of Brca1 directly to the DNA break site where it facilitates DSB repair; 2) ATM phosphorylates histone protein H2AX, resulting in formation of γH2AX domains in the DSB flanking regions that serve as a platform for MDC1 and RNF8 recruitment; 3) RNF8 and RNF186 E3 ubiquitin ligases facilitate the conjugation of ubiquitin chains to the histone H2A; 4) Rap80 links Brca1 to these poly-ubiquitin chains, thus recruiting a larger Brca1 fraction to the DSB flanking chromatin; 5) Brca1 recruitment to the flanking chromatin increases the amount of Brca1 molecules interacting with active ATM, resulting in an efficient phosphorylation of Brca1 at serine residues 1387 and 1423, which is required for the activation of S-phase and G₂/M checkpoints, respectively; 6) The Rap80/Brca1 complex residing in the DSB flanking regions also represses an excessive DSB processing, thus tuning HR.