Rad17 recruits the MRE11-RAD50-NBS1 complex to regulate the cellular response to DNA double-strand breaks.

Published

Journal Article

The MRE11-RAD50-NBS1 (MRN) complex is essential for the detection of DNA double-strand breaks (DSBs) 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 MDC1 and contributes to ATM activation. Mechanistically, Rad17 is phosphorylated by ATM at a novel Thr622 site resulting in a direct interaction of Rad17 with NBS1, 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 MDC1-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.

Full Text

Duke Authors

Cited Authors

  • Wang, Q; Goldstein, M; Alexander, P; Wakeman, TP; Sun, T; Feng, J; Lou, Z; Kastan, MB; Wang, X-F

Published Date

  • April 16, 2014

Published In

Volume / Issue

  • 33 / 8

Start / End Page

  • 862 - 877

PubMed ID

  • 24534091

Pubmed Central ID

  • 24534091

Electronic International Standard Serial Number (EISSN)

  • 1460-2075

Digital Object Identifier (DOI)

  • 10.1002/embj.201386064

Language

  • eng

Conference Location

  • England