2025-04-29 中国科学院(CAS)
<関連情報>
- https://english.cas.cn/newsroom/research_news/life/202504/t20250427_1042075.shtml
- https://www.cell.com/cell/abstract/S0092-8674(25)00414-3
染色体外DNAの複製と維持が腫瘍におけるDNA損傷経路と連関していることが明らかになった Extrachromosomal DNA replication and maintenance couple with DNA damage pathway in tumors
Xing Kang ∙ Xinran Li ∙ Jiaqi Zhou ∙ … ∙ Zhike Zi ∙ Xiangyu Liu ∙ Haiyun Gan
Cell Published:April 28, 2025
DOI:https://doi.org/10.1016/j.cell.2025.04.012
Graphical abstract
Highlights
- ecDNA replication-dependent activation of ATM and DDR ensures ecDNA maintenance
- TOP1 and TOP2B are critical regulators of ecDNA-induced DDR
- Alt-NHEJ pathway promotes ecDNA maintenance
- ATM-mediated DDR is a promising therapeutic target for treating ecDNA+ tumors
Summary
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.
