BRCA1-Dependent and Independent Recruitment of PALB2-BRCA2-RAD51 in the DNA Damage Response and Cancer

The BRCA1-PALB2-BRCA2 axis plays essential roles in the cellular response to DNA double-strand breaks (DSB), mainte-nance of genome integrity, and suppression of cancer develop-ment. Upon DNA damage, BRCA1 is recruited to DSBs, where it facilitates end resection and recruits PALB2 and its associated BRCA2 to load the central recombination enzyme RAD51 to initiate homologous recombination (HR) repair. In recent years, several BRCA1-independent mechanisms of PALB2 recruitment have also been reported. Collectively, these available data illus-trate a series of hierarchical, context-dependent, and cooperating mechanisms of PALB2 recruitment that is critical for HR and therapy response either in the presence or absence of BRCA1. Here, we review these BRCA1-dependent and independent mechanisms and their importance in DSB repair, cancer devel-opment, and therapy. As BRCA1-mutant cancer cells regain HR function, for which PALB2 is generally required, and become resistant to targeted therapies, such as PARP inhibitors, targeting BRCA1-independent mechanisms of PALB2 recruitment repre-sents a potential new avenue to improve treatment of BRCA1-mutant tumors.

Automated summary

The BRCA1-PALB2-BRCA2 axis is crucial for DNA damage repair, genome integrity maintenance, and cancer suppression. Besides the BRCA1-dependent mechanism, alternative mechanisms of PALB2 recruitment have been identified. Targeting BRCA1-independent mechanisms of PALB2 recruitment may provide a new avenue for improving treatment of BRCA1-mutant tumors.