A Bifunctional Role for the UHRF1 UBL Domain in the Control of Hemi-methylated DNA-Dependent Histone Ubiquitylation

Mol Cell. 2018 Nov 15;72(4):753-765.e6. doi: 10.1016/j.molcel.2018.09.029. Epub 2018 Nov 1.


DNA methylation patterns regulate gene expression programs and are maintained through a highly coordinated process orchestrated by the RING E3 ubiquitin ligase UHRF1. UHRF1 controls DNA methylation inheritance by reading epigenetic modifications to histones and DNA to activate histone H3 ubiquitylation. Here, we find that all five domains of UHRF1, including the previously uncharacterized ubiquitin-like domain (UBL), cooperate for hemi-methylated DNA-dependent H3 ubiquitin ligation. Our structural and biochemical studies, including mutations found in cancer genomes, reveal a bifunctional requirement for the UBL in histone modification: (1) the UBL makes an essential interaction with the backside of the E2 and (2) the UBL coordinates with other UHRF1 domains that recognize epigenetic marks on DNA and histone H3 to direct ubiquitin to H3. Finally, we show UBLs from other E3s also have a conserved interaction with the E2, Ube2D, highlighting a potential prevalence of interactions between UBLs and E2s.

Keywords: DNA methylation; RING; RING E3 ligase; SRA; UBL; UHRF1; epigenetics; hemi-methylated DNA; histone H3 ubiquitylation; ubiquitin; ubiquitin-like domain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • DNA / genetics
  • DNA / metabolism
  • DNA Methylation*
  • Epigenesis, Genetic
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Protein Binding
  • Protein Domains
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination


  • CCAAT-Enhancer-Binding Proteins
  • Histones
  • DNA
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNMT1 protein, human
  • UHRF1 protein, human
  • Ubiquitin-Protein Ligases