数字农科院2.0

Extrachromosomal DNA replication and maintenance couple with DNA damage pathway in tumors

文献类型： 外文期刊

作者： Kang, Xing;Li, Xinran;Zhou, Jiaqi;Zhang, Yang;Qiu, Lingyu;Tian, Congcong;Deng, Zhiwen;Liang, Xiaoyan;Zhang, Ziwei;Du, Songlin;Hu, Suili;Wang, Nan;Yue, Zhen;Xu, Yajing;Gao, Yuan;Dai, Junbiao;Wang, Zhiquan;Yu, Chuanhe;Chen, Jinyi;Wu, Yuchun;Chen, Liangming;Yao, Yuan;Yao, Sitong;Yang, Xinran;Yan, Lixia;Wen, Qing;Depies, Olivia M.;Chan, Kuiming;Liang, Xiaohuan;Li, Gang;Zi, Zhike;Liu, Xiangyu;Gan, Haiyun

作者机构：

期刊名称： CELL

ISSN： 0092-8674

年卷期： 2025 年 188 卷 13 期

页码：

收录情况： SCIE（2025版）

摘要： Extrachromosomal DNA (ecDNA) drives the evolution of cancer cells. However, the functional significance of ecDNA and the molecular components involved in its replication and maintenance remain largely unknown. Here, using CRISPR-C technology, we generated ecDNA-carrying (ecDNA+) cell models. By leveraging these models alongside other well-established systems, we demonstrated that ecDNA can replicate and be maintained in ecDNA+ cells. The replication of ecDNA activates the ataxia telangiectasia mutated (ATM)-mediated DNA damage response (DDR) pathway. Topoisome rases, such as TOP1 and TOP2B, play a role in ecDNA replication-induced DNA double-strand breaks (DSBs). A subset of these elevated DSBs persists into the mitotic phase and is primarily repaired by the alternative non-homologous end joining (alt-NHEJ) pathway, which involves POLO and LIG3. Correspondingly, ecDNA maintenance requires DDR, and inhibiting DDR impairs the circularization of ecDNA. In summary, we demonstrate reciprocal interactions between ecDNA maintenance and DDR, providing new insights into the detection and treatment of ecDNA+ tumors.

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