Mechanism of Cross-talk between H2B Ubiquitination and H3 Methylation by Dot1L.
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.
['Worden|Evan J|EJ|', 'Hoffmann|Niklas A|NA|', 'Hicks|Chad W|CW|', 'Wolberger|Cynthia|C|']
D000818:Animals D020134:Catalytic Domain D002843:Chromatin D011495:Histone-Lysine N-Methyltransferase D006657:Histones D006801:Humans D008745:Methylation D008958:Models, Molecular D009707:Nucleosomes D011499:Protein Processing, Post-Translational D020239:Receptor Cross-Talk D025801:Ubiquitin D054875:Ubiquitination D014982:Xenopus laevis
ubiquitin methylation histones Dot1L cryo-EM nucleosome chromatin structural biology