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

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

Author information

1
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: cwolberg@jhmi.edu.

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.

KEYWORDS:

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

PMID:
30765112
PMCID:
PMC6498860
[Available on 2020-03-07]
DOI:
10.1016/j.cell.2019.02.002

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