Cell
Volume 176, Issue 6, 7 March 2019, Pages 1490-1501.e12
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Article
Mechanism of Cross-talk between H2B Ubiquitination and H3 Methylation by Dot1L

https://doi.org/10.1016/j.cell.2019.02.002Get rights and content
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Highlights

  • Cryo-EM structures of Dot1L methyltransferase bound to H2B-ubiquitinated nucleosomes

  • Dot1L bound in poised and active states contacts the ubiquitin I36 hydrophobic patch

  • The tail of histone H4 binds in a cleft in Dot1L.

  • A conformational change is induced in histone H3 that enables Dot1L to access H3K79

Summary

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

chromatin
ubiquitin
histones
methylation
Dot1L
nucleosome
cryo-EM
structural biology

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