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Disruption of microhomology-mediated end joining in Ewing sarcoma

Shuhei Asada1, Guangli Zhu2, Jithma Prasad Abeykoon3

  • 1Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Molecular Cell
|July 21, 2026
PubMed

Insights

Ewing sarcoma (EwS) cells show impaired DNA repair due to the EWS-FLI1 oncoprotein. This defect in microhomology-mediated end joining (MMEJ) DNA repair offers potential therapeutic targets for EwS treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Ewing sarcoma (EwS) is a pediatric bone and soft-tissue cancer.
  • EwS cells are sensitive to DNA damaging agents, suggesting a role for DNA repair pathways.
  • The EWS-FLI1 oncoprotein is implicated in EwS pathogenesis.

Purpose of the Study:

  • To investigate the role of EWS-FLI1 in DNA repair mechanisms in Ewing sarcoma.
  • To identify potential therapeutic vulnerabilities in EwS based on DNA repair defects.

Main Methods:

  • Assessed microhomology-mediated end joining (MMEJ) repair activity in EwS cells.
  • Investigated the effect of EWS-FLI1 expression and EWSR1 depletion on MMEJ.
  • Analyzed POLQ pre-mRNA splicing and Polθ expression.
  • Evaluated cellular sensitivity to DNA repair pathway inhibitors.

Main Results:

  • EWS-FLI1 expression causes a defect in MMEJ DNA repair.
  • EWS-FLI1 disrupts EWSR1-mediated splicing of POLQ, leading to reduced Polθ expression and impaired MMEJ.
  • EwS cells exhibit synthetic lethality with inhibitors of Fanconi anemia (FA), homologous recombination (HR), or non-homologous end joining (NHEJ) pathways.
  • Restoring POLQ splicing corrected MMEJ function in EwS cells.

Conclusions:

  • EWS-FLI1 impairs MMEJ DNA repair in Ewing sarcoma by affecting POLQ splicing.
  • Targeting FA, HR, or NHEJ pathways represents a potential therapeutic strategy for EwS.
  • Understanding DNA repair defects in EwS can guide the development of novel cancer treatments.
Keywords:
CDK12DNA double-strand breaksDNA-PKcEwing sarcomaRBM39TMEJalternative end joining

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