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Updated: Jul 11, 2025

Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
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Disparate pathways for extrachromosomal DNA biogenesis and genomic DNA repair

John C Rose1, Ivy Tsz-Lo Wong2,3, Bence Daniel1,3

  • 1Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.

Biorxiv : the Preprint Server for Biology
|November 14, 2023
PubMed

Insights

Extrachromosomal DNA (ecDNA) formation in cancer involves efficient DNA circularization through end joining mechanisms. DNA repair pathway inhibition differentially affects ecDNA and excision scar formation, revealing distinct biogenesis dynamics.

Area of Science:

  • Cancer Biology
  • Genetics
  • Molecular Biology

Background:

  • Oncogene amplification on extrachromosomal DNA (ecDNA) is a key driver in cancer development.
  • The precise mechanisms of ecDNA biogenesis remain poorly understood.

Approach:

  • A CRISPR-based system was employed to induce and study ecDNA formation.
  • Extensive characterization of newly formed ecDNA was performed using advanced techniques.

Key Points:

  • DNA circularization to form ecDNA is highly efficient and independent of 3D genome organization.
  • Both non-homologous end joining and microhomology-mediated end joining contribute to ecDNA formation.
  • Inhibition of DNA-PKcs and ATM kinases differentially impacts ecDNA and chromosomal excision scar formation.

Conclusions:

  • A model is proposed where double-strand break ends dissociate and re-ligate non-homologously to form ecDNA and excision scars.
  • EcDNA and its corresponding chromosomal excision scar exhibit distinct formation rates and responses to DNA repair inhibition.
  • Understanding ecDNA biogenesis provides insights into cancer evolution and potential therapeutic targets.

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