Cell-Cycle Regulation of BRCA1 Inhibits Homologous Recombination in G1

The tumor suppressors BRCA1, partner and localizer of BRCA2 (PALB2), and BRCA2 form a complex that promotes DNA double-strand break (DSB) repair by homologous recombination, which is repressed in G1 cells; however, the mechanism by which homologous recombination is suppressed is unknown. Orthwein, Noordermeer, and colleagues showed that recruiting BRCA1 to DSBs during G1 by mutating tumor protein p53 binding protein1 (53BP1) did not result in the recruitment of BRCA2 or PALB2. PALB2 interacted with BRCA2 throughout the cell cycle, but interacted with BRCA1 only during S phase, suggesting that the cell cycle controls the assembly of the BRCA1–PALB2–BRCA2 complex and prevents BRCA2 from localizing to DSBs outside of the S/G2 phases. The domain of PALB2 that interacts with kelch-like ECH-associated protein 1 (KEAP1) was required for the cell-cycle–dependent regulation of the BRCA1–PALB2 interaction. KEAP1, a substrate adaptor for a cullin 3–RING ubiquitin ligase (CRL3), was found to ubiquitylate lysine residues 20, 25, and 30 in the N-terminus of PALB2, which blocked its interaction with BRCA1 and prevented the assembly of the BRCA1–PALB2–BRCA2 complex in G1 phase. Ubiquitin specific peptidase 11 (USP11) removed ubiquitin from PALB2, promoting BRCA1–PALB2–BRCA2 complex formation. USP11 rapidly turned over in G1 cells, consistent with the loss of the BRCA1–PALB2–BRCA2 complex. Homologous recombination could be triggered in G1 cells, but required both activation of DNA-end resection and BRCA2 recruitment to DSBs. These findings reveal that the assembly of the BRCA1–PALB2–BRCA2 complex is an essential step in controlling the cell-cycle regulation of homologous recombination, and indicate that suppression of homologous recombination during G1 phase is reversible, which may have implications for therapeutic gene targeting in nondividing cells.

Orthwein A, Noordermeer SM, Wilson MD, Landry S, Enchev RI, Sherker A, et al. A mechanism for the suppression of homologous recombination in G1 cells. Nature 2015;528:422–6.

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