PIN1 isomerisation of BRCA1 promotes replication fork protection.

BRCA1, BRCA2 and a subset of Fanconi9s Anaemia proteins act to promote RAD51-mediated protection of newly synthesised DNA at stalled replication forks from degradation by nucleases. How BRCA1 contributes, how it is regulated and whether replication fork protection relates to, or differs from, the roles BRCA1 has in homologous recombination is not clear. Here we show that the canonical BRCA1-PALB2 interaction is not required for fork protection and instead we demonstrate that the ability of BRCA1 to protect nascent DNA is regulated in an unexpected fashion through conformational change mediated by the phosphorylation-directed prolyl isomerase, PIN1. BRCA1 isomerisation enhances BRCA1-BARD1 interaction with RAD51 and consequently RAD51 presence at stalled replication structures. Patient missense variants in the regulated BRCA1-BARD1 regions similarly show poor nascent strand protection but proficient homologous recombination, defining novel domains required for fork protection in BRCA1-BARD1 associated with cancer predisposition. Together these findings reveal a previously unrecognised pathway that governs BRCA1-mediated replication fork protection.