Protein phosphatase 2A controls ongoing DNA replication by binding to and regulating cell division cycle 45 (CDC45)

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Genomic replication is crucial for cell division but requires precise regulation.
• Post-translational modifications governing replication are not fully understood.
• Protein phosphatase 2A (PP2A) is a key regulator of diverse cellular processes.

Purpose of the Study:

• To investigate the role of PP2A in regulating genomic replication.
• To elucidate the mechanisms by which PP2A activity affects DNA replication.
• To determine PP2A's involvement in maintaining genomic integrity.

Main Methods:

• Utilized gain-of-function chemical biology and loss-of-function genetic approaches to modulate PP2A activity.
• Investigated PP2A's interaction with replication factors like CDC45.
• Analyzed genomic alterations in individuals with PP2A gene mutations.

Main Results:

• Increased PP2A activity interrupts DNA replication, prolonging S phase and causing replication fork collapse.
• PP2A activity induces double-strand DNA breaks, homologous recombination, and a replication stress response.
• PP2A forms complexes with CDC45 during replication, and its increased activity dissociates CDC45 and polymerase α from the replisome.
• PP2A gene mutations correlate with increased genomic alterations.

Conclusions:

• PP2A plays a novel role in regulating ongoing DNA replication.
• PP2A activity is essential for maintaining genomic integrity by preventing replication stress.
• PP2A may be involved in the intra-S-phase checkpoint.