Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation
S K Reddy1, M Rape, W A Margansky
1Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|April 20, 2007
Summary
Cellular spindle checkpoints ensure accurate chromosome segregation by inhibiting the anaphase-promoting complex (APC). Inactivation involves APC-dependent multi-ubiquitination, releasing inhibition and allowing cell division.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Eukaryotic cells utilize the spindle checkpoint for accurate chromosome segregation.
- This checkpoint prevents sister chromatid separation until kinetochores achieve bipolar spindle attachment.
- Checkpoint proteins inhibit the anaphase-promoting complex (APC), a ubiquitin ligase crucial for mitosis.
Purpose of the Study:
- To elucidate the mechanism by which cells switch from spindle checkpoint inhibition to rapid activation.
- To understand how chromosome segregation is promptly initiated after kinetochore attachment.
- To explore potential reasons for compromised spindle checkpoints in cancer cells.
Main Methods:
- Investigated the role of APC-dependent multi-ubiquitination in checkpoint inactivation.
- Examined the dissociation of checkpoint proteins (Mad2, BubR1) from Cdc20.
- Identified a de-ubiquitinating enzyme that reverses Cdc20 ubiquitination.
Main Results:
- Spindle checkpoint inactivation is an energy-dependent process involving APC-mediated multi-ubiquitination.
- Multi-ubiquitination causes Mad2 and BubR1 to detach from Cdc20, enabling APC activation.
- A de-ubiquitinating enzyme reverses this process, highlighting a regulatory cycle.
Conclusions:
- The interplay between checkpoint proteins and APC ensures timely chromosome segregation.
- This mechanism allows cells to rapidly activate the APC once kinetochore attachment is complete.
- Findings provide a basis for understanding spindle checkpoint defects in cancer without direct mutations.
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