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CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation

Tarek Abbas1, Etsuko Shibata, Jonghoon Park

  • 1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.

Molecular Cell
|October 12, 2010
PubMed

Insights

The CRL4(Cdt2) E3 ubiquitin ligase degrades the Set8 enzyme during the S phase, maintaining epigenetic stability. Disrupting this process causes DNA damage and cell cycle delays.

Area of Science:

  • Epigenetics
  • Cell Cycle Regulation
  • Ubiquitin Ligase Function

Background:

  • PR-Set7/Set8 is a cell-cycle-regulated enzyme.
  • It monomethylates histone H4 at lysine 20 (H4K20).
  • Set8 and H4K20 levels rise in late S and G2 phases.

Purpose of the Study:

  • To identify the E3 ubiquitin ligase responsible for Set8 degradation during the S phase.
  • To investigate the consequences of disrupting the Set8 degradation pathway.

Main Methods:

  • Identification of CRL4(Cdt2) as the E3 ligase for Set8.
  • Analysis of Set8-PCNA interaction.
  • Assessment of cellular responses upon inactivation of the CRL4-Cdt2-PCNA-Set8 axis.

Main Results:

  • CRL4(Cdt2) targets Set8 for degradation in S phase via PCNA interaction.
  • Inactivation led to DNA damage, p53 induction, and apoptosis.
  • Cell cycle G2/M checkpoint activation caused delayed G2 progression.
  • Histone and E2F1-dependent gene transcription were repressed.

Conclusions:

  • CRL4(Cdt2)-mediated regulation of Set8 is crucial for maintaining epigenetic stability.
  • This pathway is essential for cell viability and proper cell cycle progression.

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