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

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

  • Cell. 2025 Jun 26;188(13):3405-3421.e27. doi: 10.1016/j.cell.2025.04.012.
Xing Kang 1,  Xinran Li 2,  Jiaqi Zhou 1,  Yang Zhang 1,  Lingyu Qiu 1,  Congcong Tian 1,  Zhiwen Deng 3,  Xiaoyan Liang 1,  Ziwei Zhang 1,  Songlin Du 4,  Suili Hu 5,  Nan Wang 1,  Zhen Yue 1,  Yajing Xu 5,  Yuan Gao 6,  Junbiao Dai 7,  Zhiquan Wang 8,  Chuanhe Yu 9,  Jinyi Chen 1,  Yuchun Wu 10,  Liangming Chen 1,  Yuan Yao 1,  Sitong Yao 5,  Xinran Yang 1,  Lixia Yan 2,  Qing Wen 1,  Olivia M Depies 8,  Kuiming Chan 11,  Xiaohuan Liang 12,  Gang Li 13,  Zhike Zi 1,  Xiangyu Liu 3,  Haiyun Gan 14
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Synthetic Genomics, Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 2 Guangdong Provincial Key Laboratory of Synthetic Genomics, Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, China.
  • 4 College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang 712100, Shaanxi, China.
  • 5 Guangdong Provincial Key Laboratory of Synthetic Genomics, Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
  • 6 Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, OH, USA.
  • 7 CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics and Shenzhen Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Key Laboratory of Synthetic Biology, Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.
  • 8 Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
  • 9 Hormel Institute, University of Minnesota, Austin, MN, USA.
  • 10 Guangdong Provincial Key Laboratory of Synthetic Genomics, Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; School of Basic Medicine, Qingdao University, Qingdao, China.
  • 11 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
  • 12 College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
  • 13 Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China.
  • 14 Guangdong Provincial Key Laboratory of Synthetic Genomics, Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. Electronic address: hy.gan@siat.ac.cn.
PMID: 40300601 DOI: 10.1016/j.cell.2025.04.012
Abstract

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.

Keywords

DNA damage response; LIG3; TOP1; TOP2B; alt-NHEJ; ecDNA.

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