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

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

doi:10.1016/j.cell.2025.04.012

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

Xing Kang (Co-first Author)
, Xinran Li (Co-first Author)
, Jiaqi Zhou (Co-first Author)
, Yang Zhang (Co-first Author)
, Lingyu Qiu (Co-first Author)
, Congcong Tian (Co-first Author)
, Zhiwen Deng (Co-first Author)
, Xiaoyan Liang
, Ziwei Zhang
, Songlin Du
, Suili Hu
, Nan Wang
, Zhen Yue
, Yajing Xu
, Yuan Gao
, Junbiao Dai
, Zhiquan Wang
, Chuanhe Yu
, Jinyi Chen
, Yuchun Wu

Liangming Chen, Yuan Yao, Sitong Yao, Xinran Yang, Lixia Yan, Qing Wen, Olivia M. Depies, Kuiming Chan, Xiaohuan Liang, Gang Li, Zhike Zi, Xiangyu Liu, Haiyun Gan^*

^*Corresponding author for this work

Department of Biomedical Sciences

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

30 Citations (Scopus)

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. © 2025 Elsevier Inc.

Original language	English
Pages (from-to)	3405-3421.e27
Journal	Cell
Volume	188
Issue number	13
Online published	28 Apr 2025
DOIs	https://doi.org/10.1016/j.cell.2025.04.012
Publication status	Published - 26 Jun 2025

Funding

This work was funded by grants from the National Key R&D Program of China (grant no. 2019YFA0903800 to H.G.), the Major Program of the National Natural Science Foundation of China (32090031 to H.G.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0480000 to H.G.), the General Program of the National Natural Science Foundation of China (32070610 to H.G.), the Guangdong Province Fund for Distinguished Young Scholars (2021B1515020109 to H.G.), the National Natural Science Foundation of China for Young Scholars (32000580 to Q.W., 32100460 to J.Z., 32101178 to Y.Y., 32400470 to C.T., and 32400482 to L.Q.), the Guangdong Basic and Applied Basic Research Foundation (2021A1515110377 to X.K., 2021A1515110483 to N.W., and 2024A1515012730 to C.T.), the Guangdong Provincial Key Laboratory of Synthetic Genomics (2023B1212060054 to H.G.), the Shenzhen Science and Technology Program (JCYJ20230807140602005 to X.Y.), the Shenzhen Medical Research Fund (A2403039 to C.T.), the Shenzhen Key Laboratory of Synthetic Genomics (ZDSYS201802061806209 to H.G.), the China Postdoctoral Science Foundation (2021M703381 to X.K. and 2021M693306 to N.W.), and the SIAT Innovation Program for Excellent Young Researchers (E1G071 to N.W.).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Keywords

alt-NHEJ
DNA damage response
ecDNA
LIG3
TOP1
TOP2B

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@article{3a7d463a9d344faeb07cd288f040c4c7,

title = "Extrachromosomal DNA replication and maintenance couple with DNA damage pathway in tumors",

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. {\textcopyright} 2025 Elsevier Inc.",

keywords = "alt-NHEJ, DNA damage response, ecDNA, LIG3, TOP1, TOP2B",

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

year = "2025",

month = jun,

day = "26",

doi = "10.1016/j.cell.2025.04.012",

language = "English",

volume = "188",

pages = "3405--3421.e27",

journal = "Cell",

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Kang, X, Li, X, Zhou, J, Zhang, Y, Qiu, L, Tian, C, Deng, Z, Liang, X, Zhang, Z, Du, S, Hu, S, Wang, N, Yue, Z, Xu, Y, Gao, Y, Dai, J, Wang, Z, Yu, C, Chen, J, Wu, Y, Chen, L, Yao, Y, Yao, S, Yang, X, Yan, L, Wen, Q, Depies, OM, Chan, K, Liang, X, Li, G, Zi, Z, Liu, X & Gan, H 2025, 'Extrachromosomal DNA replication and maintenance couple with DNA damage pathway in tumors', Cell, vol. 188, no. 13, pp. 3405-3421.e27. https://doi.org/10.1016/j.cell.2025.04.012

TY - JOUR

T1 - Extrachromosomal DNA replication and maintenance couple with DNA damage pathway in tumors

AU - Kang, Xing

AU - Li, Xinran

AU - Zhou, Jiaqi

AU - Zhang, Yang

AU - Qiu, Lingyu

AU - Tian, Congcong

AU - Deng, Zhiwen

AU - Liang, Xiaoyan

AU - Zhang, Ziwei

AU - Du, Songlin

AU - Hu, Suili

AU - Wang, Nan

AU - Yue, Zhen

AU - Xu, Yajing

AU - Gao, Yuan

AU - Dai, Junbiao

AU - Wang, Zhiquan

AU - Yu, Chuanhe

AU - Chen, Jinyi

AU - Wu, Yuchun

AU - Chen, Liangming

AU - Yao, Yuan

AU - Yao, Sitong

AU - Yang, Xinran

AU - Yan, Lixia

AU - Wen, Qing

AU - Depies, Olivia M.

AU - Chan, Kuiming

AU - Liang, Xiaohuan

AU - Li, Gang

AU - Zi, Zhike

AU - Liu, Xiangyu

AU - Gan, Haiyun

PY - 2025/6/26

Y1 - 2025/6/26

N2 - 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. © 2025 Elsevier Inc.

AB - 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. © 2025 Elsevier Inc.

KW - alt-NHEJ

KW - DNA damage response

KW - ecDNA

KW - LIG3

KW - TOP1

KW - TOP2B

UR - https://www.scopus.com/pages/publications/105003772316

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-105003772316&origin=recordpage

U2 - 10.1016/j.cell.2025.04.012

DO - 10.1016/j.cell.2025.04.012

M3 - RGC 21 - Publication in refereed journal

SN - 0092-8674

VL - 188

SP - 3405-3421.e27

JO - Cell

JF - Cell

IS - 13

ER -

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

Abstract

Funding

UN SDGs

Research Keywords

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