Molecular cell · 2026
Disruption of microhomology-mediated end joining in Ewing sarcoma.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Asada Shuhei, Zhu Guangli, Abeykoon Jithma Prasad, Tanaka Yutaro, Nguyen Huy, Hirohashi Yuna, Iyer Divya R, Ashton Nicholas William, Mukkavalli Sirisha, Velazquez Martha, Jiang Lige, Del Busso Miles, Thangaiah Judith Jebastin, Robinson Steven I, Parmar Kalindi, Van Allen Eliezer M, Gillani Riaz, Shapiro Geoffrey I, D'Andrea Alan D
Аннотация
Ewing sarcoma (EwS) is a group of bone and soft-tissue cancers in children and young adults. Because EwS cells have pronounced sensitivity to radiation and chemotherapy-induced DNA damage, the oncoprotein EWS-FLI1 is likely to be involved in DNA repair. Here, we demonstrate that EWS-FLI1 causes a defect in microhomology-mediated end joining (MMEJ) repair. EWSR1 is a splicing factor that promotes the faithful splicing of the POLQ pre-mRNA, required for the expression of Polθ, a critical protein in the MMEJ pathway. Expression of EWS-FLI1 or depletion of EWSR1 causes increased POLQ exon 25 skipping, decreased Polθ expression, impaired MMEJ, and enhanced cellular sensitivity to inhibitors of the Fanconi anemia (FA), homologous recombination (HR), or non-homologous end joining (NHEJ) pathways, through the mechanism of synthetic lethality. Correction of POLQ exon 25 skipping restored Polθ expression and MMEJ activity in EwS. Inhibitors of the FA, HR, or NHEJ pathways may therefore provide a targeted therapy for EwS patients.