USP7 is a SUMO deubiquitinase essential for DNA replication

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Post-translational modifications, including ubiquitination (Ub) and SUMOylation, regulate DNA replication.
• Chromatin near replisomes is SUMO-rich and Ub-poor, while mature chromatin shows the reverse.
• Mechanisms maintaining this SUMO-rich, Ub-poor environment at replication sites are unknown.

Purpose of the Study:

• To investigate the mechanisms maintaining the SUMO-rich, Ub-poor environment at DNA replication sites in mammalian cells.
• To identify proteins essential for regulating SUMO and Ub balance around replisomes.

Main Methods:

• Identification of replisome-enriched proteins.
• Biochemical assays to assess deubiquitinase activity on SUMOylated proteins.
• Inhibition and genetic deletion of USP7.
• Analysis of protein localization around replication forks.

Main Results:

• USP7 was identified as a replisome-enriched SUMO deubiquitinase essential for DNA replication.
• USP7 counteracts the ubiquitination of SUMO and SUMOylated proteins.
• USP7 inhibition or deletion caused Ub accumulation on SUMOylated proteins, leading to their displacement from replisomes.

Conclusions:

• USP7 plays a critical role in maintaining the SUMO-rich, Ub-poor environment at replication forks.
• USP7's function is essential for efficient DNA replication.
• USP7's role in DNA replication warrants consideration for developing USP7 inhibitors as anticancer agents.