title: Rad17 recruits the MRE11-RAD50-NBS1 complex to regulate the cellular response to DNA double-strand breaks.
abstract: 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Qinhong
authors.initials: Q
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Goldstein
authors.forename: Peter
authors.initials: P
authors.lastname: Alexander
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Wakeman
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.forename: Junjie
authors.initials: J
authors.lastname: Feng
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kastan
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
mesh_terms: D017766:Acid Anhydride Hydrolases; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; C113575:Rad17 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes