EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex

Mol Cell. 2012 Nov 30;48(4):572-86. doi: 10.1016/j.molcel.2012.09.004. Epub 2012 Oct 11.


Ubiquitination plays a major role in protein degradation. Although phosphorylation-dependent ubiquitination is well known for the regulation of protein stability, methylation-dependent ubiquitination machinery has not been characterized. Here, we provide evidence that methylation-dependent ubiquitination is carried out by damage-specific DNA binding protein 1 (DDB1)/cullin4 (CUL4) E3 ubiquitin ligase complex and a DDB1-CUL4-associated factor 1 (DCAF1) adaptor, which recognizes monomethylated substrates. Molecular modeling and binding affinity studies reveal that the putative chromo domain of DCAF1 directly recognizes monomethylated substrates, whereas critical binding pocket mutations of the DCAF1 chromo domain ablated the binding from the monomethylated substrates. Further, we discovered that enhancer of zeste homolog 2 (EZH2) methyltransferase has distinct substrate specificities for histone H3K27 and nonhistones exemplified by an orphan nuclear receptor, RORα. We propose that EZH2-DCAF1/DDB1/CUL4 represents a previously unrecognized methylation-dependent ubiquitination machinery specifically recognizing "methyl degron"; through this, nonhistone protein stability can be dynamically regulated in a methylation-dependent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / metabolism*
  • Cullin Proteins / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Enhancer of Zeste Homolog 2 Protein
  • Humans
  • MCF-7 Cells
  • Methylation
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism
  • Polycomb Repressive Complex 2 / metabolism*
  • Protein-Serine-Threonine Kinases
  • Substrate Specificity
  • Ubiquitin-Protein Ligases / metabolism*


  • CUL4A protein, human
  • Carrier Proteins
  • Cullin Proteins
  • DDB1 protein, human
  • DNA-Binding Proteins
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • RORA protein, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • Ubiquitin-Protein Ligases
  • DCAF1 protein, human
  • Protein-Serine-Threonine Kinases