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Functional interplay between p53 acetylation and H1.2 phosphorylation in p53-regulated transcription

K Kim1, K W Jeong, H Kim

  • 1Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.

Oncogene
|January 18, 2012
PubMed

Insights

Histone H1.2 normally suppresses gene activity, but its repression of p53 is reversed by p53 acetylation and H1.2 phosphorylation, activating DNA damage responses.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Epigenetics

Background:

  • Linker histone H1.2 modulates chromatin remodeling to suppress p53-dependent transcription.
  • Mechanisms underlying H1.2's antagonistic effects in DNA damage response remain unclear.

Purpose of the Study:

  • Investigate the regulatory mechanisms controlling H1.2's repressive function on p53 during DNA damage.
  • Elucidate how post-translational modifications of p53 and H1.2 impact their interaction and p53 activity.

Main Methods:

  • Assessed the impact of p53 acetylation and H1.2 phosphorylation on the p53-H1.2 interaction.
  • Utilized point mutations to mimic specific modification states of p53 and H1.2.
  • Measured p53-dependent transcriptional activity and apoptosis induction.

Main Results:

  • p53 acetylation by p300 disrupts p53-H1.2 binding, leading to p53 transcriptional activation.
  • DNA-PK-mediated phosphorylation of H1.2 at T146 also impairs H1.2 binding to p53, enhancing transcriptional activity.
  • Mutations mimicking these modifications significantly increased p53-induced apoptosis.

Conclusions:

  • A p53 acetylation-H1.2 phosphorylation cascade regulates H1.2's suppressive role in DNA damage response.
  • This cascade acts as a critical switch for activating p53-dependent DNA damage pathways.
  • Findings reveal a novel mechanism for fine-tuning the cellular response to DNA damage.

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