Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53

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.