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Rad17 recruits the MRE 11‐ RAD 50‐ NBS 1 complex to regulate the cellular response to DNA double‐strand breaks
Author(s) -
Wang Qinhong,
Goldstein Michael,
Alexander Peter,
Wakeman Timothy P,
Sun Tao,
Feng Junjie,
Lou Zhenkun,
Kastan Michael B,
Wang XiaoFan
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/embj.201386064
Subject(s) - rad50 , biology , microbiology and biotechnology , dna repair , dna damage , homologous recombination , g2 m dna damage checkpoint , dna , cell cycle checkpoint , phosphorylation , dna binding protein , genetics , cell cycle , cell , transcription factor , gene
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.