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Related Experiment Videos

DNA damage activates p53 through a phosphorylation-acetylation cascade

K Sakaguchi1, J E Herrera, S Saito

  • 1Laboratory of Cell Biology, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland 20892, USA.

Genes & Development
|September 23, 1998
PubMed
Summary

DNA damage triggers p53 acetylation and phosphorylation, enhancing its transcription factor activity. This study reveals how specific modifications by p300 and PCAF HATs regulate p53 DNA binding and cellular response.

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Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • p53 is a critical transcription factor responding to DNA damage.
  • Post-translational modifications like phosphorylation and acetylation regulate p53 activity.
  • Histone acetyltransferases (HATs) are key regulators of protein acetylation.

Purpose of the Study:

  • To investigate the roles of p300 and PCAF in p53 acetylation.
  • To determine how acetylation and phosphorylation affect p53 DNA-binding activity.
  • To elucidate the interplay between p53 acetylation and phosphorylation in response to DNA damage.

Main Methods:

  • In vitro acetylation assays using purified p53 and HATs (p300, PCAF).
  • Site-directed mutagenesis to identify acetylation sites (Lys-382, Lys-320).

Related Experiment Videos

  • Western blot analysis using specific antibodies to detect in vivo phosphorylation and acetylation after UV or ionizing radiation exposure.

    • Main Results:

    • p300 acetylates Lys-382 (carboxy-terminus) and PCAF acetylates Lys-320 (nuclear localization signal) of p53 in vitro.
    • Acetylation at either site enhances p53 sequence-specific DNA binding.
    • In vivo, Lys-382 acetylation and Ser-33/Ser-37 phosphorylation occur after DNA damage.
    • Amino-terminal phosphorylation differentially affects p53 acetylation by p300 and PCAF.

    Conclusions:

    • DNA damage enhances p53 transcriptional activity via carboxy-terminal acetylation.
    • Amino-terminal phosphorylation of p53 directs its carboxy-terminal acetylation by specific HATs.
    • This coordinated regulation of p53 by phosphorylation and acetylation is crucial for the DNA damage response.