PIKK-dependent phosphorylation of Mre11 induces MRN complex inactivation by disassembly from chromatin.
The role of Mre11 phosphorylation in the cellular response to DNA double-strand breaks (DSBs) is not well understood. Here, we show that phosphorylation of Mre11 at SQ/TQ motifs by PIKKs (PI3 Kinase-related Kinases) induces MRN (Mre11-Rad50-Nbs1) complex dissociation from chromatin by reducing Mre11 affinity for DNA. Whereas phosphorylation of Mre11 at these residues is not required for DSB-induced ATM (Ataxia-Telangiectasia mutated) activation, abrogation of Mre11 dephosphorylation impairs ATM signaling. Our study provides a functional characterization of the DNA damage-induced Mre11 phosphorylation, and suggests that MRN inactivation participates in the down-regulation of damage signaling during checkpoint recovery following DSB repair.
PubMed ID: 19709933
PMC ID: PMC2764007
Article link: DNA Repair (Amst).
Grant support: CA92245 NCI NIH HHS , R01 CA092245-08 NCI NIH HHS , R01 GM077495-02 NIGMS NIH HHS , R01 CA092245 NCI NIH HHS , R01 GM077495 NIGMS NIH HHS
Genes referenced: atm mre11a nbn rad50