Mre11-Rad50-dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1.
The Mre11-Rad50-Nbs1 (MRN) protein complex and ATM/Tel1 kinase protect genome integrity through their functions in DNA double-strand break (DSB) repair, checkpoint signaling, and telomere maintenance. Nbs1 has a conserved C-terminal motif that binds ATM/Tel1, but the full extent and significance of ATM/Tel1 interactions with MRN are unknown. Here, we show ... that Tel1 overexpression bypasses the requirement for Nbs1 in DNA damage signaling and telomere maintenance. These activities require Mre11-Rad50, which localizes to DSBs and bind Tel1 in the absence of Nbs1. Fusion of the Tel1-binding motif of Nbs1 to Mre11 is sufficient to restore Tel1 signaling in nbs1? cells. Tel1 overexpression does not restore Tel1 signaling in cells carrying the rad50-I1192W mutation, which impairs the ability of Mre11-Rad50 to form the ATP-bound closed conformation. From these findings, we propose that Tel1 has a high-affinity interaction with the C-terminus of Nbs1 and a low-affinity association with Mre11-Rad50, which together accomplish efficient localization and activation of Tel1 at DSBs and telomeres.
Mesh Terms:
Adenosine Triphosphate, DNA Breaks, Double-Stranded, Mutation, Protein Binding, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Signal Transduction, Telomere
Adenosine Triphosphate, DNA Breaks, Double-Stranded, Mutation, Protein Binding, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Signal Transduction, Telomere
Mol. Biol. Cell
Date: Dec. 01, 2017
PubMed ID: 29851556
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