In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators

Area of Science:

• Cell Biology
• Molecular Biology
• Epigenetics

Background:

• The anaphase-promoting complex/cyclosome (APC/C) is a crucial E3 ubiquitin ligase controlling cell cycle progression.
• Identifying APC/C substrates is vital for understanding cell cycle control but remains challenging.

Purpose of the Study:

• To globally map APC/C substrates using computational predictions and experimental validation.
• To investigate the role of APC/C in regulating chromatin proteins during the cell cycle.

Main Methods:

• In silico prediction of APC/C substrates based on known substrate features.
• Experimental validation of predicted substrates, including binding assays and cell cycle analysis.
• Detailed mechanistic studies on UHRF1 ubiquitylation and degradation.

Main Results:

• Successfully predicted numerous known and novel APC/C substrates.
• Identified a significant enrichment of chromatin regulatory proteins among APC/C targets.
• Demonstrated that several chromatin proteins bind APC/C, oscillate during the cell cycle, and are degraded post-APC/C activation.
• Elucidated UHRF1 ubiquitylation mechanisms and showed its degradation impacts cell cycle progression and DNA methylation.

Conclusions:

• APC/C plays a critical role in coordinating cell cycle progression with the regulation of chromatin proteins.
• This crosstalk is essential for normal cell physiology and may have implications in disease states.
• APC/C-mediated regulation of chromatin proteins, like UHRF1, influences fundamental processes such as DNA methylation maintenance.