Singh, S.; Maurya, A. K.; Mohapatra, I.; Kim, S.; Naqvi, A. R.; Singh, G.; Chen, C. C.

Repair of ionizing-radiation (IR)-induced membrane damage is essential for cell survival, and Annexin A2 (ANXA2) mediates this repair by promoting shedding of microvesicles containing both damaged lipid and ANXA2. Here, we show that coupling this process to microRNA export contributes to radiation resistance of glioblastoma, the most common adult brain cancer. Structural modeling and mutational analysis identify that ANXA2 tyrosine 23 (Y23) phosphorylation, required for its IR-induced localization to damaged membranes, is also essential for binding miR-603, a critical regulator of glioblastoma cell state. This binding is required for IR-induced miR-603 export, indicating that the repair program recruiting ANXA2 also positions it to load miR-603 into microvesicles. Mutations that abolish ROS-induced sulfenylation and activation of SRC (SRC-C185A/C245A) suppressed ANXA2-Y23 phosphorylation, microvesicle shedding, and miR-603 export. The epistatic interaction between ANXA2-Y23A, SRC-C185A/C245A, and miR-603 delineates a therapeutically targetable radiation-response network that couples membrane repair with miRNA export.