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

Nat Cell Biol. 2006 Nov;8(11):1277-83. doi: 10.1038/ncb1490. Epub 2006 Oct 15.

Abstract

The CUL4-DDB1-ROC1 ubiquitin E3 ligase regulates cell-cycle progression, replication and DNA damage response. However, the substrate-specific adaptors of this ligase remain uncharacterized. Here, we show that CUL4-DDB1 complexes interact with multiple WD40-repeat proteins (WDRs) including TLE1-3, WDR5, L2DTL (also known as CDT2) and the Polycomb-group protein EED (also known as ESC). WDR5 and EED are core components of histone methylation complexes that are essential for histone H3 methylation and epigenetic control at K4 or K9 and K27, respectively, whereas L2DTL regulates CDT1 proteolysis after DNA damage through CUL4-DDB1 (ref. 8). We found that CUL4A-DDB1 interacts with H3 methylated mononucleosomes and peptides. Inactivation of either CUL4 or DDB1 impairs these histone modifications. However, loss of WDR5 specifically affects histone H3 methylation at K4 but not CDT1 degradation, whereas inactivation of L2DTL prevents CDT1 degradation but not histone methylation. Our studies suggest that CUL4-DDB1 ligases use WDR proteins as molecular adaptors for substrate recognition, and modulate multiple biological processes through ubiquitin-dependent proteolysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Chromatin / metabolism
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • HeLa Cells
  • Heterotrimeric GTP-Binding Proteins / genetics
  • Heterotrimeric GTP-Binding Proteins / metabolism*
  • Histone-Lysine N-Methyltransferase
  • Histones / metabolism*
  • Humans
  • Methylation
  • Molecular Sequence Data
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Binding
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Transfection
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CUL4A protein, human
  • Chromatin
  • Cullin Proteins
  • DDB1 protein, human
  • DNA-Binding Proteins
  • DTL protein, human
  • Histones
  • Nuclear Proteins
  • RNA, Small Interfering
  • Repressor Proteins
  • TLE1 protein, human
  • TLE2 protein, human
  • WDR5 protein, human
  • Histone-Lysine N-Methyltransferase
  • Ubiquitin-Protein Ligases
  • Heterotrimeric GTP-Binding Proteins

Associated data

  • GENBANK/EF011612
  • GENBANK/EF011613
  • GENBANK/EF011614
  • GENBANK/EF011615
  • GENBANK/EF011616
  • GENBANK/EF011617
  • GENBANK/EF011618
  • GENBANK/EF011619
  • GENBANK/EF011620
  • GENBANK/EF011621
  • GENBANK/EF011622
  • GENBANK/EF011623
  • GENBANK/EF011624