A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest

Area of Science:

• Cellular biology
• Molecular biology
• DNA damage response

Background:

• Cellular responses to stimuli can exhibit distinct early and late phases.
• The transcription factor p53 is central to the DNA damage response, influencing cell cycle arrest, repair, or apoptosis.
• The evolution of p53 dynamics and cellular outcomes under continuous DNA damage is not well understood.

Purpose of the Study:

• To investigate how p53 responses and cellular outcomes change over time in the presence of continuous DNA damage.
• To identify the molecular mechanisms driving late-phase cellular responses to DNA damage.

Main Methods:

• Monitoring of p53 dynamics in cells subjected to continuous DNA damage.
• Analysis of cell cycle progression in the context of DNA damage.
• Investigation of the role of the caspase-2-PIDDosome complex and MDM2 in p53 stabilization.

Main Results:

• A subset of cells transitions from oscillating to sustained p53 dynamics several days post-damage.
• This switch is linked to cell cycle progression despite the presence of damaged DNA.
• Activation of the caspase-2-PIDDosome complex stabilizes p53 by inhibiting MDM2.

Conclusions:

• A novel molecular pathway is defined, activated when canonical cell cycle checkpoints fail to prevent mitosis in damaged cells.
• This pathway involves the caspase-2-PIDDosome and leads to p53 stabilization, influencing cellular fate.
• The findings reveal a mechanism for evolved cellular responses to persistent DNA damage.