Histone

Gene

Cell biology

Biology

Histone octamer

DNA methylation

Histone H2B

Histone code

Chromatosome

Genetics

Histone methylation

Histone methyltransferase

Histone H3

Histone H1

Nucleosome

Gene expression

Histone H2A

Cell

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.

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