Replication Stress Causes Mitotic Nuclear Envelope Reassembly Defect

Replication stress, if not effectively and timely addressed, could result in DNA damage in mitosis. However, it remains unknown the relationship between mitotic DNA damage and other mitotic events such as nuclear envelope (NE) breakdown and reassembly. Here we report that replication stress could generate NE rupture. Rather than de novo formation, the rupture per se is a result of nuclear envelope reassembly defect (NERD) in mitosis. Repair of mitotic DNA damage by DNA polymerase theta (Polθ), a key microhomology-mediated end joining (MMEJ) factor, suppresses NERD. Furthermore, exacerbated NERD is observed in multiple conditions of synthetic lethality, suggesting NERD might be a general consequence of synthetic lethality. In addition, genomic mapping of LADs identifies a population of RESS-LADs (replication stress-sensitive LADs). Replication stress causes the loss of CFSs at RESS-LADs, likely due to the sustained phosphorylation of Lamin A/C at the NE rupture sites. Altogether, our findings establish a novel link between replication stress-induced genome instability and nuclear vulnerability.