DNA damage regulates UHRF1 stability via the SCF(β-TrCP) E3 ligase

Area of Science:

• Epigenetics
• Molecular Biology
• Cancer Biology

Background:

• UHRF1 is essential for DNA methylation maintenance and its dysregulation is linked to cancer.
• While UHRF1 stabilization by USP7 is known, its ubiquitylation and degradation pathways remain unclear.

Purpose of the Study:

• To elucidate the mechanism of UHRF1 ubiquitylation and proteasomal degradation.
• To identify the E3 ligase responsible for UHRF1 degradation and its regulatory factors.

Main Methods:

• Bioinformatic analysis and mutagenesis studies to identify degron motifs.
• Co-immunoprecipitation assays to study protein interactions.
• In vitro kinase assays and Western blotting to assess protein phosphorylation and degradation.

Main Results:

• Identified a functional DSG degron in the N terminus of UHRF1 essential for stability.
• Demonstrated that SCF(β-TrCP) is the E3 ligase mediating UHRF1 degradation.
• Showed that CK1δ-catalyzed phosphorylation of S108(UHRF1) is critical for β-TrCP1 binding and subsequent degradation.
• Observed accelerated UHRF1 degradation upon DNA damage, correlated with increased S108(UHRF1) phosphorylation.

Conclusions:

• SCF(β-TrCP) is a key E3 ligase regulating UHRF1 stability.
• Phosphorylation of S108(UHRF1) by CK1δ is a critical step in UHRF1 degradation.
• This regulatory axis is important for controlling UHRF1 levels under normal conditions and in response to DNA damage.