Continuous nuclear envelope surveillance is required for DNA double-strand break repair.

Abstract Precise double-strand break (DSB) repair is paramount for genome stability. Homologous recombination (HR) is preferred to repair DSBs when a nearby sister chromatid ensures an error-free template. In Saccharomyces cerevisiae, this preference extends into anaphase and telophase (late mitosis; late-M), despite sister chromatids having been pulled apart. Previously, we identified the nuclear envelope (NE) protein Msc1 as important for late-M DSB repair. Here, we report that Msc1 faces the NE lumen, and its depletion leads to DSB-independent over-compartmentalization of the nucleus, which hampers approximation of sister loci after DSB. Depletion of Msc1 also leads to nuclear pore complex mislocation, a phenotype shared by the highly conserved NE healing complex ESCRT-III. Critically, we show that both Msc1 and ESCRT-III also ensure DSB repair in G2/M, and that there is synergism between Msc1 and the ESCRT-III subunit Snf7. These findings highlight the essential role of NE health in DSB repair.