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Updated: Apr 12, 2026
Analysis of Cell Cycle Position in Mammalian Cells
Published on: January 21, 2012
Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53
A Desantis1, T Bruno1, V Catena2
1Epigenetics Laboratory, Regina Elena National Cancer Institute, Via E. Chianesi 53, Rome, 00144, Italy.
Abstract:
The tumor suppressor p53 is mainly involved in the transcriptional regulation of a large number of growth-arrest- and apoptosis-related genes. However, a clear understanding of which factor/s influences the choice between these two opposing p53-dependent outcomes remains largely elusive. We have previously described that in response to DNA damage, the RNA polymerase II-binding protein Che-1/AATF transcriptionally activates p53. Here, we show that Che-1 binds directly to p53. This interaction essentially occurs in the first hours of DNA damage, whereas it is lost when cells undergo apoptosis in response to posttranscriptional modifications. Moreover, Che-1 sits in a ternary complex with p53 and the oncosuppressor Brca1. Accordingly, our analysis of genome-wide chromatin occupancy by p53 revealed that p53/Che1 interaction results in preferential transactivation of growth arrest p53 target genes over its pro-apoptotic target genes. Notably, exposure of Che-1(+/-) mice to ionizing radiations resulted in enhanced apoptosis of thymocytes, compared with WT mice. These results confirm Che-1 as an important regulator of p53 activity and suggest Che-1 to be a promising yet attractive drug target for cancer therapy.
Insights
The Che-1 protein directly binds to the tumor suppressor p53, influencing its choice between growth arrest and apoptosis. This interaction favors growth arrest, suggesting Che-1 as a potential cancer therapy target.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- The tumor suppressor p53 regulates genes involved in growth arrest and apoptosis.
- The precise factors determining p53's outcome (arrest vs. apoptosis) are not fully understood.
- Che-1 (AATF) was previously identified as a transcriptional activator of p53.
Purpose of the Study:
- To investigate the direct interaction between Che-1 and p53.
- To determine the functional consequences of the p53-Che-1 interaction on p53 target gene transactivation.
- To evaluate Che-1's role in vivo in response to DNA damage.
Main Methods:
- Co-immunoprecipitation to assess protein-protein interactions.
- Chromatin immunoprecipitation sequencing (ChIP-seq) for genome-wide p53 occupancy analysis.
- Assessment of thymocyte apoptosis in Che-1(+/-) and wild-type mice following irradiation.
Main Results:
- Che-1 directly binds to p53 during the early hours of DNA damage, dissociating as cells enter apoptosis.
- Che-1 forms a ternary complex with p53 and Brca1.
- p53/Che-1 interaction preferentially activates growth arrest genes over pro-apoptotic genes.
- Che-1(+/-) mice exhibit increased thymocyte apoptosis after ionizing radiation exposure.
Conclusions:
- Che-1 is a direct regulator of p53 activity, modulating its choice between growth arrest and apoptosis.
- The p53-Che-1 interaction favors cell cycle arrest, counteracting p53-mediated apoptosis.
- Che-1 represents a potential therapeutic target for cancer treatment.
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