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

Publication ,  Journal Article
Wang, Q; Goldstein, M; Alexander, P; Wakeman, TP; Sun, T; Feng, J; Lou, Z; Kastan, MB; Wang, X-F
Published in: EMBO J
April 16, 2014

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.

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Published In

EMBO J

DOI

EISSN

1460-2075

Publication Date

April 16, 2014

Volume

33

Issue

8

Start / End Page

862 / 877

Location

England

Related Subject Headings

  • Signal Transduction
  • Protein Processing, Post-Translational
  • Protein Multimerization
  • Protein Binding
  • Phosphorylation
  • Nuclear Proteins
  • MRE11 Homologue Protein
  • Humans
  • Developmental Biology
  • DNA-Binding Proteins
 

Citation

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Wang, Q., Goldstein, M., Alexander, P., Wakeman, T. P., Sun, T., Feng, J., … Wang, X.-F. (2014). Rad17 recruits the MRE11-RAD50-NBS1 complex to regulate the cellular response to DNA double-strand breaks. EMBO J, 33(8), 862–877. https://doi.org/10.1002/embj.201386064
Wang, Qinhong, Michael Goldstein, Peter Alexander, Timothy P. Wakeman, Tao Sun, Junjie Feng, Zhenkun Lou, Michael B. Kastan, and Xiao-Fan Wang. “Rad17 recruits the MRE11-RAD50-NBS1 complex to regulate the cellular response to DNA double-strand breaks.EMBO J 33, no. 8 (April 16, 2014): 862–77. https://doi.org/10.1002/embj.201386064.
Wang Q, Goldstein M, Alexander P, Wakeman TP, Sun T, Feng J, et al. Rad17 recruits the MRE11-RAD50-NBS1 complex to regulate the cellular response to DNA double-strand breaks. EMBO J. 2014 Apr 16;33(8):862–77.
Wang, Qinhong, et al. “Rad17 recruits the MRE11-RAD50-NBS1 complex to regulate the cellular response to DNA double-strand breaks.EMBO J, vol. 33, no. 8, Apr. 2014, pp. 862–77. Pubmed, doi:10.1002/embj.201386064.
Wang Q, Goldstein M, Alexander P, Wakeman TP, Sun T, Feng J, Lou Z, Kastan MB, Wang X-F. Rad17 recruits the MRE11-RAD50-NBS1 complex to regulate the cellular response to DNA double-strand breaks. EMBO J. 2014 Apr 16;33(8):862–877.

Published In

EMBO J

DOI

EISSN

1460-2075

Publication Date

April 16, 2014

Volume

33

Issue

8

Start / End Page

862 / 877

Location

England

Related Subject Headings

  • Signal Transduction
  • Protein Processing, Post-Translational
  • Protein Multimerization
  • Protein Binding
  • Phosphorylation
  • Nuclear Proteins
  • MRE11 Homologue Protein
  • Humans
  • Developmental Biology
  • DNA-Binding Proteins