Rad17 recruits the MRE 11‐ RAD 50‐ NBS 1 complex to regulate the cellular response to DNA double‐strand breaks

The MRE 11‐ RAD 50‐ NBS 1 ( MRN ) complex is essential for the detection of DNA double‐strand breaks ( DSB s) and initiation of DNA damage signaling. Here, we show that Rad17, a replication checkpoint protein, is required for the early recruitment of the MRN complex to the DSB site that is independent of MDC 1 and contributes to ATM activation. Mechanistically, Rad17 is phosphorylated by ATM at a novel Thr622 site resulting in a direct interaction of Rad17 with NBS 1, facilitating recruitment of the MRN complex and ATM to the DSB , thereby enhancing ATM signaling. Repetition of these events creates a positive feedback for Rad17‐dependent activation of MRN / ATM signaling which appears to be a requisite for the activation of MDC 1‐dependent MRN complex recruitment. A point mutation of the Thr622 residue of Rad17 leads to a significant reduction in MRN / ATM signaling and homologous recombination repair, suggesting that Thr622 phosphorylation is important for regulation of the MRN / ATM signaling by Rad17. These findings suggest that Rad17 plays a critical role in the cellular response to DNA damage via regulation of the MRN / ATM pathway.