Structural basis of recognition and destabilization of the histone H2B ubiquitinated nucleosome by the DOT1L histone H3 Lys79 methyltransferase

Seongmin Jang; Chanshin Kang; Han-Sol Yang; Taeyang Jung; Hans Hebert; Ka Young Chung; Seung Joong Kim; Sungchul Hohng; Ji-Joon Song

doi:10.1101/gad.323790.118

Structural basis of recognition and destabilization of the histone H2B ubiquitinated nucleosome by the DOT1L histone H3 Lys79 methyltransferase

¹Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea;
²Department of Physics and Astronomy, Seoul National University, Seoul 08826, Korea;
³School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea;
⁴School of Engineering Sciences in Chemistry, Biotechnology, and Health, Department of Biomedical Engineering and Health Systems, KTH Royal Institute of Technology, S-141 52 Huddinge, Sweden;
⁵Department of Biosciences and Nutrition, Karolinska Institutet, S-141 52 Huddinge, Sweden;
⁶Department of Physics, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea

Corresponding author: songj{at}kaist.ac.kr

Abstract

DOT1L is a histone H3 Lys79 methyltransferase whose activity is stimulated by histone H2B Lys120 ubiquitination, suggesting cross-talk between histone H3 methylation and H2B ubiquitination. Here, we present cryo-EM structures of DOT1L complexes with unmodified or H2B ubiquitinated nucleosomes, showing that DOT1L recognizes H2B ubiquitin and the H2A/H2B acidic patch through a C-terminal hydrophobic helix and an arginine anchor in DOT1L, respectively. Furthermore, the structures combined with single-molecule FRET experiments show that H2B ubiquitination enhances a noncatalytic function of the DOT1L-destabilizing nucleosome. These results establish the molecular basis of the cross-talk between H2B ubiquitination and H3 Lys79 methylation as well as nucleosome destabilization by DOT1L.

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Footnotes

Supplemental material is available for this article.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.323790.118.

Received December 30, 2018.
Accepted March 8, 2019.

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