SCF cyclin F - EXO1 axis controls cell cycle dependent execution of double strand break repair

Ubiquitination is a crucial post-translational modification required for the proper repair of DNA double-strand breaks (DSBs) induced by ionising radiation (IR). DSBs are mainly repaired through homologous recombination (HR) when template DNA is present and non-homologous end joining (NHEJ) in its absence. Additionally, microhomology-mediated end joining (MMEJ) and single strand annealing (SSA) provide back-up DSBs repair pathways. However, the mechanisms controlling their use remain poorly understood. By employing a high-resolution CRISPR screen of the ubiquitin system after IR, we systematically uncover genes required for cell survival and elucidate a critical role of the E3 ubiquitin ligase SCFcyclin F in cell cycle-dependent DSB repair. We show that SCFcyclin F -mediated EXO1 degradation prevents DNA end resection in mitosis, allowing MMEJ to take place. Moreover, we identify a conserved cyclin F recognition motif, distinct from the one used by other cyclins, with broad implications in cyclin specificity for cell cycle control.