Abstract
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. Unanticipated conformational plasticity in the globular core of histone H3 underlies cross-talk between histone modifications.
Original language | English (US) |
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Pages (from-to) | 1490-1501.e12 |
Journal | Cell |
Volume | 176 |
Issue number | 6 |
DOIs | |
State | Published - Mar 7 2019 |
Keywords
- Dot1L
- chromatin
- cryo-EM
- histones
- methylation
- nucleosome
- structural biology
- ubiquitin
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology