The RNA-binding protein RALY promotes ATM activation by stabilizing Tip60.

A rapid DNA damage response (DDR) and efficient DNA repair are essential for maintaining genome integrity. As a central apical kinase, ATM phosphorylates multiple downstream substrates to initiate DDR signaling and coordinate DNA repair following double-strand breaks (DSBs). However, the precise molecular mechanisms underlying ATM activation remain incompletely understood. Here, we identify the RNA-binding protein RALY as a critical regulator of ATM activation. We show that RALY directly interacts with and stabilizes the acetyltransferase Tip60, a key activator of ATM. Mechanistically, RALY competes with Tip60 for binding to the E3 ubiquitin ligase Mdm2, thereby inhibiting Mdm2-mediated ubiquitination and degradation of Tip60. Functionally, inhibition of RALY impairs ATM activation, compromises DNA repair capacity, and enhances radiosensitivity of cancer cells in a Tip60-dependent manner. Our findings uncover a previously unrecognized role of RALY in regulating ATM activation and indicate RALY as a potential therapeutic target for enhancing radiosensitivity in cancer.