Disruption of Microhomology-mediated End-joining in Ewing Sarcoma.

ABSTRACT: Ewing sarcoma (EwS) is a group of bone and soft tissue cancers in children and young adults. The EWS-FLI1 protein, the oncogenic driver in EwS, is a fusion of the FET protein, EWSR1, at its amino terminus, with the carboxy terminus of the transcription factor, FLI1. Since EwS cells have pronounced sensitivity to radiation and chemotherapy-induced DNA damage, the role of EWS-FLI1 in DNA repair is likely. 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 loss of EWSR1, causes exon 25 skipping of the POLQ transcript, decreased POLΘ protein

SUBMITTER: Asada S 

PROVIDER: S-EPMC12191234 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature