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

Abstract

The BRCA1-PALB2-BRCA2 axis plays essential roles in the cellular response to DNA double-strand breaks (DSB), maintenance of genome integrity, and suppression of cancer development. 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 illustrate 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 development, 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 represents a potential new avenue to improve treatment of BRCA1-mutant tumors.

Figure 1.

Domain structures of BRCA1, BARD1, PALB2 and BRCA2. Their key interacting partners involved in the DNA damage response are shown and their binding sites indicated. The triple lines between BRCA1 and BARD1 indicate a stoichiometric complex formation of the two proteins. NCP, nucleosome core particle.

Figure 2.

HR initiation upon DSB formation and mechanisms of PALB2-BRCA2-RAD51 recruitment under different conditions. (A) Cartoon showing steps of HR initiation and the involvement of the relevant proteins in this review. (B-E) Cartoons showing PALB2-BRCA2 recruitment and the extent of RAD51 loading in cells with different BRCA1 and 53BP1 status. Panel B illustrates “canonical” PALB2 recruitment in normal cells by a direct interaction with BRCA1, with RNF168 serving as a stabilizing factor aside from its function as a histone E3 ligase; panel C depicts a blockade of PALB2 recruitment by 53BP1 and associated proteins in BRCA1 null cells; panel D shows recruitment of PALB2 through its interaction with RNF168 and the nucleosome core particle (via ChAM) in BRCA1/53BP1 double null cells; and panel E shows residual PALB2 recruitment by RNF168 in cells with disrupted PALB2-BRCA1 interaction. MRG15-mediated PALB2 tethering to actively transcribed chromatin regions (marked by H3K36me3) is also shown in B. A BRCA1 CC mutation affecting BRCA1-PALB2 interaction is indicated as a red dot in E. See text for details.