Mitotic DNA repair by TMEJ suppresses replication stress-induced nuclear envelope reassembly defect

Guojun Ye, Yide He, Yihui Zhang, Dongchen Li, Fuhai Liu, Yi Li, Qinglian Ge, Qiong Guo, Shuya Han, Chunyu Song, Weiping Chang, Haoyue Zhang, Qin Peng, Kun Sun, Weike Ji and Lin Deng ()
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Guojun Ye: Capital Medical University
Yide He: Shenzhen Bay Laboratory
Yihui Zhang: Shenzhen Bay Laboratory
Dongchen Li: Shenzhen Bay Laboratory
Fuhai Liu: Shenzhen Bay Laboratory
Yi Li: Shenzhen Bay Laboratory
Qinglian Ge: Capital Medical University
Qiong Guo: Capital Medical University
Shuya Han: Capital Medical University
Chunyu Song: Capital Medical University
Weiping Chang: Shenzhen Bay Laboratory
Haoyue Zhang: Shenzhen Bay Laboratory
Qin Peng: Shenzhen Bay Laboratory
Kun Sun: Shenzhen Bay Laboratory
Weike Ji: Huazhong University of Science and Technology
Lin Deng: Shenzhen Bay Laboratory

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Replication stress (RS), if not effectively and timely addressed, could result in DNA damage in mitosis. However, the relationship between RS and other mitotic events, such as nuclear envelope (NE) breakdown and reassembly, remains poorly understood. Here we report that RS can lead to NE defect. Importantly, rather than de novo NE rupture, the defect per se is a result of nuclear envelope reassembly defect (NERD) during mitosis. Interestingly, NERD is associated with mitotic DNA damage, and repair of the damage by DNA polymerase theta (Polθ)-mediated end joining (TMEJ) ameliorates NERD. Genomic mapping of lamina associated domains (LADs) by cleavage under targets and tagmentation (CUT&Tag) identifies a population of replication stress-sensitive LADs (RESSLADs). Strikingly, a substantial portion of RESSLADs reside in the common fragile sites (CFSs). The loss of RESSLADs-NE interaction under RS might be attributed to the sustained phosphorylation of Lamin A/C at the sites of NERD. In addition, prominent NE defect is observed under multiple conditions of synthetic lethality. Altogether, these findings establish a link between genome instability and nuclear vulnerability under replication stress.

Date: 2025
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DOI: 10.1038/s41467-025-63942-w

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