Mol Cell | 朱广李等揭示尤文肉瘤中EWS-FLI1通过双重机制摧毁POLQ剪接与功能，导致MMEJ缺陷

TL;DR - A Molecular Cell study identifies Ewing sarcoma as an MMEJ-deficient cancer and shows that EWS-FLI1 disables POLQ/Pol θ through defective exon 25 splicing and impaired DNA-repair foci formation. This creates targetable dependencies on alternative DNA-repair pathways and may provide a biomarker for treatment selection.

• EWSR1, FUBP1, and KHSRP normally bind a six-nucleotide enhancer in POLQ exon 25 to preserve correct splicing and functional Pol θ expression.
• EWS-FLI1 sequesters EWSR1 away from this enhancer, causing exon 25 skipping, while independently disrupting Pol θ recruitment to mitotic DNA-break sites.
• Correcting POLQ splicing restored MMEJ activity and reversed sensitivity to DNA-repair inhibitors, establishing a direct causal link.
• Ewing sarcoma models were selectively vulnerable to RBM39 degraders, CDK12 inhibitors, and DNA-PK inhibition combined with etoposide.