Non-homologous end joining (NHEJ) is particularly important for repair of double-strand breaks (DSBs) in the G1 stage of the cell cycle, when there is no homologous chromosome to act as a template for repair by homologous recombination. How the correct repair pathway is set up is unclear, but previous work suggested opposing roles for the homologous recombination factor BRCA1 and the NHEJ protein 53BP1 in end resection, an early step in homologous recombination. Several recent studies have now shed light on this mechanism.

The groups of de Lange (Science 339, 700–704; 2013 ), Nussenzweig (Science 339, 711–715; 2013 ), Durocher (Mol. Cell http://doi.org/kgk; 2013) and Boulton (Mol. Cell http://doi.org/kgm; 2013) all identify RIF1 as an effector of 53BP1 that is recruited to DSBs in G1 to prevent end resection. In the absence of RIF1, DSBs are hyperresected and cells show G1-specific hypersensitivity to ionizing radiation. The Boulton and Nussenzweig groups find that RIF1-null mice are deficient in class switch recombination, demonstrating a critical role for RIF1 in NHEJ in vivo. The Durocher, de Lange and Boulton groups further elucidate how RIF1 influences repair pathway choice, and find that RIF1 together with 53BP1 blocks BRCA1 recruitment in G1. Conversely, BRCA1 prevents the accumulation of RIF1 to DSBs in S or G2, and Durocher and colleagues find that the BRCA1 cofactor CtIP, phosphorylated by CDK1 (cyclin-dependent kinase 1), cooperates with BRCA1 in RIF1 exclusion in S/G2. Thus, mutual antagonism between 53BP1–RIF1 and BRCA1–CtIP ensures correct repair pathway choice.