ATM is activated by default in mitosis, localizes at centrosomes and monitors mitotic spindle integrity.
We previously showed that ATM is responsible for p53 phosphorylation at Ser15 and localization at centrosomes during mitosis. When p53 centrosomal localization is prevented by inhibiting polymerization of spindle microtubules, a stabilized form of p53 is transmitted to daughter cells that arrest in the next G(1) phase of the cell cycle after exit from mitosis. AT cells are unable to both localize p53 at centrosomes in mitosis and arrest after exposure to mitotic-spindle poisons. Here we show that during mitosis ATM is activated by phosphorylation at Ser1981 and localizes at centrosomes. When mitotic spindle is disrupted by nocodazole, ATM is displaced from centrosomes and colocalizes with phospho-Ser15-p53 under the form of spots dispersed in the mitotic cytoplasm. After release from nocodazole-block, as soon as cells exit mitosis, p53 is redirected to the nucleus and its Ser15 phosphorylation is substituted by phosphorylation at Ser46. We suggest that ATM is activated by default at each mitotic onset and phosphorylates p53 at Ser15 so as to keep it inactive at centrosomes when the spindle is correctly in place or, in case of inactivation of the mitotic spindle, to maintain the memory of a perturbed mitosis.
Oricchio
Elisa
E
Institute of Biology and Molecular Pathology, National Research Council, Rome, Italy.
Saladino
Chiara
C
Iacovelli
Stefano
S
Soddu
Silvia
S
Cundari
Enrico
E
D001260:Ataxia Telangiectasia; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008938:Mitosis; D009154:Mutation / Q000235:genetics; D010768:Phosphoserine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D010768:Phosphoserine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases