biostudies-literatureUnknownMenon SNCI NIH HHSThe genetic principle of synthetic lethality is clinically validated in cancers with loss of specific DNA damage response (DDR) pathway genes (i.e. BRCA1/2 tumor suppressor mutations). The broader question of whether and how oncogenes create tumor-specific vulnerabilities within DDR networks remains unanswered. Native FET protein family members are among the earliest proteins recruited to DNA double-strand breaks (DSBs) during the DDR, though the function of both native FET proteins and FET fusion oncoproteins in DSB repair remains poorly defined. Here we focus on Ewing sarcoma (ES), an EWS-FLI1 fusion oncoprotein-driven pediatric bone tumor, as a model for FET rearranged cancers. We discover that the EWS-FLI1 fusion oncoprotein is recruited to DNA DSBs and interferes with native EWS functResearch squarers.3.rs-2869150https://www.ebi.ac.uk/biostudies/studies/S-EPMC10312925biostudies-literatureFET fusion oncoproteins disrupt physiologic DNA repair networks and induce ATR synthetic lethality in cancer.PMC10312925R01 CA211052U54 CA224081P30 CA008748R01 CA169338R01 CA204302U01 CA217882P50 CA217694Weissman JMenon SBivona TGPerati SHeslin AAllegakoen HHorlbeck MATulpule ALin YPBreese MRSweet-Cordero EAfalseFET fusion oncoproteins disrupt physiologic DNA repair networks and induce ATR synthetic lethality in cancer.The genetic principle of synthetic lethality is clinically validated in cancers with loss of specific DNA damage response (DDR) pathway genes (i.e. BRCA1/2 tumor suppressor mutations). The broader question of whether and how oncogenes create tumor-specific vulnerabilities within DDR networks remains unanswered. Native FET protein family members are among the earliest proteins recruited to DNA double-strand breaks (DSBs) during the DDR, though the function of both native FET proteins and FET fusion oncoproteins in DSB repair remains poorly defined. Here we focus on Ewing sarcoma (ES), an EWS-FLI1 fusion oncoprotein-driven pediatric bone tumor, as a model for FET rearranged cancers. We discover that the EWS-FLI1 fusion oncoprotein is recruited to DNA DSBs and interferes with native EWS funct2023-01-01T00:00:00Z2023 May2026-04-07T15:44:26.25Z2026-04-07T14:48:51.844ZS-EPMC103129253739821010.21203/rs.3.rs-2869150/v1