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A novel human p53 isoform is an essential element of the ATR-intra-S phase checkpoint

Gabor Rohaly1, Jan Chemnitz, Silke Dehde

  • 1Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Universität Hamburg, Martinistrasse 52, D-20251, Hamburg, Germany.

Cell
|July 13, 2005
PubMed

Insights

A newly identified p53 isoform, Deltap53, shows transcriptional activity in damaged S phase cells. This tumor suppressor isoform activates the p21 gene, impacting cell cycle progression and DNA repair.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The tumor suppressor protein p53 is known for its transactivation properties.
  • Existing human p53 isoforms are generally considered transcriptionally inactive.
  • The role of p53 in DNA damage response is well-established.

Purpose of the Study:

  • To investigate the transcriptional activity of a novel p53 isoform, Deltap53.
  • To determine if Deltap53 possesses independent transactivation capabilities.
  • To elucidate the role of Deltap53 in the intra-S phase checkpoint.

Main Methods:

  • Analysis of alternative splicing in p53.
  • Reporter assays to assess promoter transactivation by p53 and Deltap53.
  • Cell cycle analysis in response to DNA damage.
  • Western blotting to detect protein expression and activity.

Main Results:

  • Deltap53, an alternatively spliced p53 isoform, exhibits transcriptional activity.
  • Deltap53 selectively transactivates p21 and 14-3-3sigma promoters, unlike p53.
  • Deltap53's activity is specific to damaged S phase cells and the ATR-intra-S phase checkpoint.
  • Deltap53-induced p21 expression downregulates cyclin A-Cdk activity, attenuating S phase progression.

Conclusions:

  • Deltap53 functions as a transcriptionally active tumor suppressor isoform.
  • The Deltap53-p21-cyclin A-Cdk pathway is critical for uncoupling DNA repair and replication.
  • Deltap53 is an essential component of the ATR-intra-S phase DNA damage checkpoint.

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