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The Cell Cycle Control System01:28

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The cell cycle regulation directs how a cell proceeds from one phase to the next and begins mitosis. The cell cycle control system includes intracellular regulatory molecules and external triggers. They provide "stop" or "advance" signals and operate at specific cell cycle stages termed checkpoints to ensure that a particular process is completed before the cell advances to the next phase.
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The cell cycle is an organized set of events that leads the cell to divide into two daughter cells, each containing chromosomes identical to the parent cell. It is the cell cycle that leads to the formation of an entire organism from a single-cell zygote. Besides, cell division also functions in the renewal or repair of tissues in adult multicellular eukaryotes. For example, in the bone marrow, the stem cells divide to form new blood cells. Although essential for several functions, cell...
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The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
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At the transition from prophase to metaphase, there is a reduction in cohesion along the chromosomal arms, resulting in the resolution of sister chromatids. However, residual cohesin connections remain to hold the sister chromatids together until the transition from metaphase to anaphase. The residual connection prevents any premature separation of sister chromatids, blocking the risks of aneuploidy within the daughter cells.
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Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
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Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression.

Michiel Boekhout1, Ruixue Yuan2, Annelotte P Wondergem2

  • 1Division of Cell Biology I (B5), The Netherlands Cancer Institute (NKI-AvL), Amsterdam, The Netherlands.

EMBO Reports
|February 17, 2016
PubMed
Summary

Atypical E2Fs (E2F7/8) are regulated by the anaphase-promoting complex/cyclosome (APC/C). This feedback loop involving APC/C(CDH1) ensures proper cell cycle gene expression and progression.

Keywords:
CDH1DNA replicationE2Fanaphase‐promoting complexcell cycle

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • E2F transcription factors regulate cell cycle gene expression.
  • Activator E2Fs (E2F1-3) promote G1-to-S transition, while atypical E2Fs (E2F7/8) downregulate targets in later phases.
  • The inactivation mechanism of atypical E2Fs remained unclear.

Purpose of the Study:

  • To investigate the inactivation mechanism of atypical E2Fs (E2F7 and E2F8).
  • To elucidate the role of the anaphase-promoting complex/cyclosome (APC/C) in regulating E2F7/8 stability and function.

Main Methods:

  • Ubiquitination assays to identify APC/C substrates.
  • Mutagenesis of KEN boxes to assess E2F7/8 stability.
  • Cell cycle analysis and cell viability assays.
  • Co-immunoprecipitation to study protein interactions.

Main Results:

  • E2F7 and E2F8 were identified as substrates of the APC/C complex.
  • Mutations in CDH1-interacting KEN boxes stabilized E2F7/8, impairing G1-to-S transition and causing cell death.
  • E2F8 interacts with APC/C(CDC20), while both E2F7/8 activate APC/C(CDH1) by repressing its inhibitors.

Conclusions:

  • A novel feedback loop exists between atypical E2Fs and APC/C(CDH1).
  • This loop is crucial for maintaining balanced cell cycle gene expression.
  • The findings reveal a critical mechanism for normal cell cycle progression.