HERC2-USP20 axis regulates DNA damage checkpoint through Claspin.

Area of Science:

• Cellular biology
• Molecular oncology
• Biochemistry

Background:

• The DNA damage response (DDR) is crucial for maintaining genomic stability.
• Post-translational modifications regulate DDR pathways, but ubiquitination's role in ATR signaling remains unclear.
• Replication stress and single-strand breaks activate ATR signaling, a key component of the DDR.

Purpose of the Study:

• To investigate the role of ubiquitination in regulating ATR signaling during replication stress.
• To identify specific deubiquitination enzymes (DUBs) involved in the ATR-dependent DDR pathway.
• To elucidate the mechanism by which USP20 influences ATR signaling and DNA repair.

Main Methods:

• Screening of deubiquitination enzymes (DUBs) to identify regulators of replication stress response.
• Investigating the interaction between USP20, HERC2, and Claspin using biochemical assays.
• Analyzing the phosphorylation of USP20 by ATR and its effect on protein stability and signaling.

Main Results:

• USP20 was identified as a critical DUB for replication stress response.
• ATR phosphorylates USP20, leading to HERC2 dissociation and USP20 stabilization.
• USP20 deubiquitinates and stabilizes Claspin, thereby enhancing ATR-Chk1 signaling activation.

Conclusions:

• USP20 is a novel and pivotal regulator of the ATR-dependent DNA damage signaling pathway.
• USP20's function in stabilizing Claspin is essential for ATR-Chk1 activation under replication stress.
• Targeting USP20 may offer new therapeutic strategies for DNA damage response-related diseases.