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CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation

Leigh Ann Higa1, Min Wu, Tao Ye

  • 1Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.

Nature Cell Biology
|October 17, 2006
PubMed

Insights

The CUL4-DDB1-ROC1 ligase uses WD40-repeat proteins as adaptors to target substrates. This mechanism regulates cell processes like DNA damage response and epigenetic control via ubiquitin-dependent proteolysis.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Biochemistry

Background:

  • The CUL4-DDB1-ROC1 ubiquitin E3 ligase is crucial for cell-cycle progression, DNA replication, and DNA damage response.
  • Substrate-specific adaptors for this ligase complex have remained largely uncharacterized.

Purpose of the Study:

  • To identify and characterize the substrate-specific adaptors of the CUL4-DDB1-ROC1 ubiquitin E3 ligase.
  • To elucidate the role of these adaptors in regulating biological processes.

Main Methods:

  • Co-immunoprecipitation assays to identify interacting WD40-repeat proteins (WDRs).
  • Functional assays to assess the impact of WDR inactivation on histone methylation and CDT1 proteolysis.
  • Analysis of CUL4A-DDB1 interaction with methylated histone peptides and mononucleosomes.

Main Results:

  • CUL4-DDB1 complexes interact with multiple WDR proteins, including WDR5, L2DTL (CDT2), and EED.
  • WDR5 is involved in histone H3 methylation at K4, while L2DTL regulates CDT1 proteolysis.
  • Inactivation of CUL4 or DDB1 affects histone modifications, but WDR5 and L2DTL have specific roles.

Conclusions:

  • WD40-repeat proteins act as molecular adaptors for CUL4-DDB1 ligase-mediated substrate recognition.
  • The CUL4-DDB1 ligase system modulates diverse biological processes, including epigenetic control and DNA repair, through ubiquitin-dependent proteolysis.

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