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.
Di Virgilio
Michela
M
Institute for Cancer Genetics, Department of Genetics and Development, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
Ying
Carol Y
CY
Gautier
Jean
J
D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D000076228:MRE11 Homologue Protein; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016415:Sequence Alignment; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D029867:Xenopus Proteins / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis / Q000378:metabolism*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C510917:Mre11 protein, Xenopus; C511600:NBN protein, Xenopus; C542167:Rad50 protein, Xenopus; D025521:Tumor Suppressor Proteins; D029867:Xenopus Proteins; D011494:Protein Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes