A FOXO-dependent replication checkpoint restricts proliferation of damaged cells

Area of Science:

• Cell Biology
• Molecular Biology
• Genomics

Background:

• DNA replication is crucial for genomic integrity but faces challenges from various factors.
• Replication stress activates checkpoints to protect the genome, but its effect on cell proliferation is debated.

Purpose of the Study:

• To investigate the mechanism by which mild replication stress restricts cell proliferation.
• To identify the role of the anaphase promoting complex/cyclosome (APC/C^CDH1) in response to replication stress.

Main Methods:

• Analysis of cell cycle progression under mild replication stress.
• Investigating the regulation of EMI1/FBXO5 levels and APC/C^CDH1 activity.
• Studying the role of Forkhead box O (FOXO) proteins and E2F1 in the response.

Main Results:

• Mild replication stress leads to premature activation of APC/C^CDH1, causing cell cycle exit.
• Replication stress decreases EMI1/FBXO5 levels via FOXO-mediated inhibition of E2F1.
• FOXO proteins limit the reversibility of the replication stress checkpoint.

Conclusions:

• A novel cell cycle exit mechanism is identified, preventing mitosis in cells experiencing mild replication stress.
• FOXO proteins play a critical role in maintaining genomic stability by regulating the replication stress response.