53BP1 Integrates DNA Repair and p53-Dependent Cell Fate Decisions via Distinct Mechanisms

Area of Science:

• Molecular Biology
• Cancer Research
• Cellular Biology

Background:

• 53BP1 is a key regulator of DNA double-strand break (DSB) repair.
• Its direct role in p53-dependent cellular functions is not well understood.

Purpose of the Study:

• To elucidate the mechanism by which 53BP1 influences p53-dependent gene expression and cellular responses.
• To determine if 53BP1's role in gene regulation is separable from its function in DSB repair.

Main Methods:

• Investigated 53BP1's interaction with p53 and USP28 using biochemical assays.
• Assessed the impact of 53BP1 mutations on p53-dependent gene transactivation and repression.
• Analyzed p53-dependent cell-cycle checkpoint and exit responses in cells with altered 53BP1 function.
• Examined 53BP1-USP28 cooperation in p53-promoter interactions and gene transactivation.

Main Results:

• 53BP1 stimulates genome-wide p53-dependent gene transactivation and repression following ionizing radiation or synthetic p53 activation.
• 53BP1-p53 interaction requires 53BP1 auto-oligomerization and bivalent BRCT domain interactions with p53 and USP28.
• Loss of these interactions impairs p53-dependent cell-cycle checkpoint and exit.
• 53BP1-USP28 cooperation is crucial for p53-promoter interactions and gene transactivation but not for DSB repair regulation.

Conclusions:

• 53BP1 and p53 cooperate to control anti-tumorigenic cell-fate decisions through distinct mechanisms.
• The gene regulatory functions of 53BP1 are separable from its role in regulating DNA double-strand break repair pathway choice.