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Potentiality of DNA-dependent protein kinase to phosphorylate Ser46 of human p53

Shingo Komiyama1, Sachiko Taniguchi, Yoshihisa Matsumoto

  • 1Department of Radiation Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Biochemical and Biophysical Research Communications
|September 24, 2004
PubMed

Insights

DNA damage triggers p53 activation. This study reveals two pathways, involving DNA-dependent protein kinase (DNA-PK) and ataxia-telangiectasia mutated (ATM), for ionizing radiation-induced p53 phosphorylation at Ser46, crucial for apoptosis.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • DNA damage response pathways are critical for maintaining genomic stability.
  • p53 protein accumulation and activation are key events following DNA damage.
  • Phosphorylation of p53, particularly at Ser46, is implicated in DNA damage-induced apoptosis, but the responsible kinases remain debated, especially following ionizing radiation (IR).

Purpose of the Study:

  • To investigate the kinases responsible for ionizing radiation (IR)-induced phosphorylation of p53 at Serine 46 (Ser46).
  • To elucidate the specific roles of DNA-dependent protein kinase (DNA-PK) and ataxia-telangiectasia mutated (ATM) in this process.

Main Methods:

  • Utilized human glioma cell lines M059K (DNA-PK proficient) and M059J (DNA-PK deficient).
  • Assessed p53 phosphorylation at Ser15, Ser37, and Ser46 following ionizing radiation (IR) exposure.
  • Investigated the direct and indirect phosphorylation capabilities of DNA-PK and ATM on p53 Ser46.

Main Results:

  • DNA-dependent protein kinase (DNA-PK) was shown to phosphorylate p53 at Ser46, in addition to previously identified sites Ser15 and Ser37.
  • IR-induced phosphorylation of p53 Ser46 occurred even in DNA-PK deficient M059J cells, suggesting alternative pathways.
  • Ataxia-telangiectasia mutated (ATM) was essential for IR-induced Ser46 phosphorylation but showed limited direct phosphorylation activity on this site.

Conclusions:

  • IR-induced phosphorylation of p53 Ser46 occurs through at least two distinct pathways.
  • One pathway involves direct phosphorylation by DNA-PK.
  • The second pathway involves indirect phosphorylation mediated by ATM.

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