Related Experiment Video
Updated: May 9, 2025
10:59
Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
3.5K
Extrachromosomal DNA replication and maintenance couple with DNA damage pathway in tumors
Xing Kang1, Xinran Li2, Jiaqi Zhou1
1Guangdong 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.
Cell
|April 29, 2025
Summary
Extrachromosomal DNA (ecDNA) replication activates DNA damage response (DDR) pathways, involving topoisomerases and DNA repair mechanisms like alt-NHEJ. This study reveals reciprocal interactions between ecDNA maintenance and DDR, offering new therapeutic strategies for ecDNA+ tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Extrachromosomal DNA (ecDNA) is a key driver of cancer evolution.
- The functional roles and molecular mechanisms governing ecDNA replication and maintenance are not fully understood.
Purpose of the Study:
- To investigate the functional significance of ecDNA in cancer cells.
- To elucidate the molecular pathways involved in ecDNA replication and maintenance.
- To explore the interplay between ecDNA and the DNA damage response (DDR).
Main Methods:
- Generation of ecDNA-carrying (ecDNA+) cell models using CRISPR-C technology.
- Utilizing established cell systems for comprehensive analysis.
- Investigating the role of topoisomerases (TOP1, TOP2B) and DNA repair pathways (alt-NHEJ, POLθ, LIG3) in ecDNA dynamics.
Main Results:
- Demonstrated that ecDNA can replicate and be maintained in ecDNA+ cells.
- Showed ecDNA replication activates the ATM-mediated DNA damage response (DDR) pathway.
- Identified topoisomerases as crucial for resolving ecDNA replication-induced DNA double-strand breaks (DSBs).
- Revealed that persistent DSBs are repaired by the alternative non-homologous end joining (alt-NHEJ) pathway.
- Established that ecDNA maintenance is dependent on DDR, with inhibition impairing ecDNA circularization.
Conclusions:
- There are reciprocal interactions between ecDNA maintenance and the DNA damage response (DDR).
- Findings provide novel insights into the biology of ecDNA.
- This research offers potential new avenues for the detection and treatment of ecDNA+ tumors.
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