Cell · 2025
Extrachromosomal DNA replication and maintenance couple with DNA damage pathway in tumors.
СтатьяНазвание и аннотация: Перевод в очереди
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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
Аннотация
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. Topoisomerases, 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 POLθ 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.