Cyclin A2 degradation during the spindle assembly checkpoint requires multiple binding modes to the APC/C

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• The anaphase-promoting complex/cyclosome (APC/C) is a crucial E3 ubiquitin ligase complex regulating cell cycle progression.
• APC/C controls the degradation of key cell cycle proteins, including cyclins A2 and B1.

Purpose of the Study:

• To investigate the mechanism of cyclin A2 ubiquitination and degradation during the cell cycle, particularly under spindle assembly checkpoint (SAC) control.
• To identify novel regulatory elements and binding modes involved in APC/C substrate recognition.

Main Methods:

• Structural analysis
• Biochemical assays
• In vivo studies
• Ubiquitination assays

Main Results:

• A non-canonical D box (D2) on cyclin A2 was identified as critical for its ubiquitination and degradation.
• During SAC, cyclin A2 is ubiquitinated by a repressed APC/C-MCC complex via its KEN and D2 boxes.
• Post-SAC, cyclin A2 exhibits differential ubiquitination efficiency through two mutually exclusive binding modes with APC/C-Cdc20.

Conclusions:

• Cyclin A2 utilizes a non-canonical D2 box for ubiquitination and degradation, distinct from the canonical D box mechanism.
• Substrate engagement with E3 ligases can occur through multiple binding modes, influencing degradation timing and efficiency.
• These findings provide new insights into the regulation of cell cycle progression by the APC/C complex.