Requirement of ATM for rapid p53 phosphorylation at Ser46 without Ser/Thr-Gln sequences.

p53 phosphorylation at Ser46 following DNA damage is important for preferential transactivation of proapoptotic genes. Here, we report that ataxia-telangiectasia mutated (ATM) kinase is responsible for Ser46 phosphorylation of p53 during early-phase response to DNA damage. To elucidate the direct phosphorylation of p53 at Ser46 by ATM, an ATM mutant ...
(ATM-AS) sensitive to ATP analogues was engineered. In vitro kinase assays revealed that p53 was phosphorylated at Ser46 by ATM-AS, even when ATP analogues were used as phosphate donors, although this phosphorylation site is not in an SQ motif, a consensus ATM site. Furthermore, Ser46 phosphorylation by ATM was dependent on the N- and C-terminal domains of p53, unlike Ser15 phosphorylation. Immunofluorescence analyses showed that Ser46-phosphorylated p53 was observed as foci in response to DNA damage and colocalized with gamma-H2AX or Ser1981-phosphorylated ATM. These results suggest that ATM phosphorylates a noncanonical serine residue on p53 by mechanisms different from those for the phosphorylation of Ser15.
Mesh Terms:
Adenosine Triphosphate, Animals, Ataxia Telangiectasia Mutated Proteins, Base Sequence, Cell Cycle Proteins, Cell Line, DNA, DNA Damage, DNA-Binding Proteins, Glutamine, Humans, Molecular Structure, Phosphorylation, Protein Serine-Threonine Kinases, RNA Interference, Recombinant Fusion Proteins, Serine, Threonine, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Mol Cell Biol
Date: Apr. 01, 2010
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