MMEJ repair of breaks at TA repeats maintains ecDNA and cancer fitness.
- Open access
Inhibition of microhomology-mediated end joining reduces ecDNA levels and impairs cancer cell fitness by targeting TA-rich breakage sites.
- Why it matters: ecDNA amplifies oncogenes, promoting aggressive tumors and therapy resistance, but the mechanisms maintaining ecDNA are poorly understood, limiting targeted treatments.
- What they did: The study used single-cell genome sequencing and molecular assays to show that disrupting MMEJ, FANCM, or Polθ causes ecDNA instability, especially at TA-rich regions, leading to ecDNA depletion.
- The result: Targeting MMEJ pathways destabilizes ecDNA, diminishes tumor growth, and offers a promising approach to sensitize ecDNA-dependent cancers to therapy.