4. Structural Basis for Recruitment of BRCA2 by PALB2

Olivier A., et al., 2009. EMBO

PALB2 is known to regulate BRCA2 to DSB, and BRCA2 is essential for RAD51 recruitment to form nucleprotein filament.

PALB2 is known as FANC-N, Fanconi anaemia subtype N
                                 130  kDa
                                 No clear functional domain other than predicted amino-terminal coiled coil structure and a carboxy-terminal WD40 repeat motif.
                                 The WD40 forms a 7 blades on PALB2 C-terminus as a ring structure. Y1183X mutation loses some C-terminal residues that inhibits the closure of the WD40 ring and destabilize PALB2 protein.

PALB2 N-terminus was thought to bind to BRCA1 to help recognize the DSB. Then, The N-terminus of BRCA2 protein interacts with PALB2 at its bottom pocket formed by the 4th and 5th blades and also interacts with EMSY protein at exactly at the same sequence. [EMSY is highly amplified and expressed in breast and ovarian cancers]. So in cancerous cells, EMSY may outcompete PALB2 at the binding site on BRCA2 to disturb the HR-mediated DNA repair.

[How???? Does BRCA2 compete with BRCA1 when BRCA1-PALB2 recognize the DSB???? or they bind at different sites or they just bind PALB2 at different stages during HR???]. BRCA2 interacts with RAD51 via the BRC repeat in the BRCA2 C-terminus. [So BRCA2-PALB2 complex is formed at the DSB to attract RAD51 over bc BRCA2 is scaffolding protein, so how does BRCA2-PALB2 complex signal for RAD51 to come to damage sites????] This BRCA2 C-terminal binding domain can revert mutant BRCA2 protein's internal deletion to  restore HR.