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Sequestration of CDH1 by MAD2L2 prevents premature APC/C activation prior to anaphase onset

Tamar Listovsky1, Julian E Sale

  • 1Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, England, UK.

The Journal of Cell Biology
|October 9, 2013
PubMed

Insights

MAD2L2 ensures accurate mitosis by controlling the sequential activation of the anaphase-promoting complex/cyclosome (APC/C). It prevents premature CDH1 binding, promoting a stable switch essential for cell division fidelity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Accurate mitosis relies on the timely activation of the anaphase-promoting complex/cyclosome (APC/C).
  • The APC/C switches from CDC20 to CDH1 activation during anaphase, a process critical for cell cycle progression.
  • APC/C(CDC20) targets specific substrates, while APC/C(CDH1) has broader substrate specificity.

Purpose of the Study:

  • To investigate the role of the APC/C inhibitor MAD2L2 in regulating the sequential activation of APC/C by CDC20 and CDH1.
  • To elucidate how MAD2L2 contributes to the metaphase-to-anaphase transition and mitotic fidelity.

Main Methods:

  • Experiments were conducted in human cells.
  • Investigated the interaction and localization of MAD2L2, CDH1, and APC/C components.
  • Analyzed the effects of MAD2L2 depletion on APC/C activity, substrate degradation, and mitotic progression.

Main Results:

  • MAD2L2 sequesters free CDH1 away from the APC/C during prometaphase.
  • APC/C(CDC20)-mediated degradation of MAD2L2 at anaphase onset releases CDH1 to activate the APC/C.
  • Loss of MAD2L2 results in premature CDH1 association with APC/C, early substrate degradation, and accelerated mitosis with aberrations.

Conclusions:

  • MAD2L2 acts as a crucial regulator, ensuring the sequential activation of APC/C by CDC20 and CDH1.
  • MAD2L2 contributes to a robust bistable switch during the metaphase-to-anaphase transition, maintaining mitotic fidelity.
  • MAD2L2's function is vital for preventing mitotic errors and ensuring accurate cell division.

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