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

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-10-03 DOI:10.1038/s41467-025-63942-w

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,Lin Deng

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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.

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TMEJ修复有丝分裂DNA抑制复制应激诱导的核膜重组缺陷。

如果不及时有效地处理复制应激，可能会导致有丝分裂过程中的DNA损伤。然而，RS与其他有丝分裂事件之间的关系，如核膜（NE）的分解和重组，仍然知之甚少。这里我们报告RS可导致NE缺陷。重要的是，该缺陷本身不是从头断裂，而是有丝分裂期间核膜重组缺陷（NERD）的结果。有趣的是，NERD与有丝分裂DNA损伤有关，DNA聚合酶θ (Polθ)介导的末端连接（TMEJ）修复损伤可改善NERD。通过切割靶和标记（CUT&Tag）对层相关结构域（LADs）进行基因组定位，确定了一个复制应激敏感的LADs （RESSLADs）群体。引人注目的是，相当一部分resslad位于常见脆弱位点（CFSs）。RS下RESSLADs-NE相互作用的丧失可能是由于NERD位点的Lamin A/C持续磷酸化。此外，在多种合成致死条件下观察到显著的NE缺陷。总之，这些发现建立了基因组不稳定性和复制压力下的核脆弱性之间的联系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.