The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53

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Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay
13:10

Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay

Published on: June 9, 2017

N D Lakin1, B C Hann, S P Jackson

  • 1Wellcome Trust/Cancer Research Campaign Institute of Cancer and Developmental Biology, Department of Zoology, Cambridge University, UK.

Oncogene
|August 6, 1999
PubMed

Insights

Researchers identified a novel DNA-activated protein kinase, ATR, that phosphorylates tumor suppressor p53 at serine-15. This discovery clarifies a key step in DNA damage signaling to p53.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • The tumor suppressor protein p53 is stabilized upon DNA damage through phosphorylation at serine-15.
  • This phosphorylation event inhibits p53's interaction with Mdm2, preventing its degradation.
  • The precise signaling pathway linking DNA damage to p53 phosphorylation remains incompletely understood.

Purpose of the Study:

  • To identify the novel DNA-activated protein kinase responsible for phosphorylating p53 at serine-15.
  • To elucidate the role of this kinase in the DNA damage response pathway.
  • To establish a biochemical assay for studying this kinase's activity.

Main Methods:

  • Fractionation of HeLa nuclear extracts.
  • Biochemical analyses to characterize kinase activity.
  • Immunoprecipitation studies using recombinant ATR.

Main Results:

  • A novel DNA-activated protein kinase was identified that phosphorylates p53 on serine-15.
  • This kinase was found to be distinct from DNA-dependent protein kinase (DNA-PK).
  • The identified kinase corresponds to the human cell cycle checkpoint protein ATR; its catalytic activity is essential for DNA-stimulated p53 phosphorylation.

Conclusions:

  • ATR functions upstream of p53 in a signal transduction cascade initiated by DNA damage.
  • ATR is the kinase responsible for phosphorylating p53 at serine-15 in response to DNA damage.
  • A biochemical assay system for ATR activity has been established.

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