The BRCA1-C complex, which includes BRCA1, BARD1, MRE11, RAD50, NBS1, and phosphorylated CtIP, plays a crucial role in the process of DNA end resection during homologous recombination repair of DNA double-strand breaks (DSBs). The synergistic enhancement of DNA end resection is primarily facilitated through specific protein-protein interactions within this complex.
Integration of Functional Domains: The interaction between BRCA1 and phosphorylated CtIP is essential for the integrity of the BRCA1-C complex. The phosphorylation of CtIP at S327 is critical for its binding to the BRCT repeats of BRCA1. This interaction not only stabilizes the complex but also enhances the recruitment of other nucleases, such as EXO1 and DNA2, which are responsible for the degradation of the 5′-terminated strands at DSB sites.
Cooperative Action of Nucleases and Helicases: BRCA1-BARD1 directly promotes long-range DNA end resection by stimulating the activity of nucleases like EXO1 and DNA2. In the DNA2-dependent pathway, BRCA1-BARD1 enhances DNA unwinding by helicases such as Werner or Bloom helicase. This cooperative action ensures efficient resection, as helicases prepare the DNA substrate for nuclease action.
Synergistic Stimulation: The presence of MRE11-RAD50-NBS1 further amplifies the resection process. The BRCA1-C complex acts synergistically, meaning that the combined effect of these proteins is greater than the sum of their individual effects. This synergy is crucial for the rapid and effective processing of DSBs, ensuring that homologous recombination can proceed efficiently.