Mechanism of Cross-talk between H2B Ubiquitination and H3 Methylation by Dot1L

Cell. 2019 Mar 7;176(6):1490-1501.e12. doi: 10.1016/j.cell.2019.02.002. Epub 2019 Feb 11.


Methylation of histone H3 K79 by Dot1L is a hallmark of actively transcribed genes that depends on monoubiquitination of H2B K120 (H2B-Ub) and is an example of histone modification cross-talk that is conserved from yeast to humans. We report here cryo-EM structures of Dot1L bound to ubiquitinated nucleosome that show how H2B-Ub stimulates Dot1L activity and reveal a role for the histone H4 tail in positioning Dot1L. We find that contacts mediated by Dot1L and the H4 tail induce a conformational change in the globular core of histone H3 that reorients K79 from an inaccessible position, thus enabling this side chain to insert into the active site in a position primed for catalysis. Our study provides a comprehensive mechanism of cross-talk between histone ubiquitination and methylation and reveals structural plasticity in histones that makes it possible for histone-modifying enzymes to access residues within the nucleosome core.

Keywords: Dot1L; chromatin; cryo-EM; histones; methylation; nucleosome; structural biology; ubiquitin.

Publication types

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

MeSH terms

  • Animals
  • Catalytic Domain
  • Chromatin / metabolism
  • Histone-Lysine N-Methyltransferase / chemistry
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histone-Lysine N-Methyltransferase / ultrastructure
  • Histones / chemistry
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Methylation
  • Models, Molecular
  • Nucleosomes / metabolism
  • Protein Processing, Post-Translational
  • Receptor Cross-Talk
  • Ubiquitin / genetics
  • Ubiquitin / metabolism
  • Ubiquitination
  • Xenopus laevis


  • Chromatin
  • Histones
  • Nucleosomes
  • Ubiquitin
  • DOT1L protein, human
  • Histone-Lysine N-Methyltransferase