Two DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids

Victoria S. Frisbie, Hideharu Hashimoto, Yixuan Xie, Francisca N. De Luna Vitorino, Josue Baeza, Tam Nguyen, Zhangerjiao Yuan, Janna Kiselar, Benjamin A. Garcia and Erik W. Debler ()
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Victoria S. Frisbie: Thomas Jefferson University
Hideharu Hashimoto: Thomas Jefferson University
Yixuan Xie: Washington University School of Medicine
Francisca N. De Luna Vitorino: Washington University School of Medicine
Josue Baeza: Perelman School of Medicine at the University of Pennsylvania
Tam Nguyen: Thomas Jefferson University
Zhangerjiao Yuan: Thomas Jefferson University
Janna Kiselar: School of Medicine
Benjamin A. Garcia: Washington University School of Medicine
Erik W. Debler: Thomas Jefferson University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract In higher eukaryotes, a single DOT1 histone H3 lysine 79 (H3K79) methyltransferase processively produces H3K79me2/me3 through histone H2B mono-ubiquitin interaction, while the kinetoplastid Trypanosoma brucei di-methyltransferase DOT1A and tri-methyltransferase DOT1B efficiently methylate the homologous H3K76 without H2B mono-ubiquitination. Based on structural and biochemical analyses of DOT1A, we identify key residues in the methyltransferase motifs VI and X for efficient ubiquitin-independent H3K76 methylation in kinetoplastids. Substitution of a basic to an acidic residue within motif VI (Gx6K) is essential to stabilize the DOT1A enzyme-substrate complex, while substitution of the motif X sequence VYGE by CAKS renders a rigid active-site loop flexible, implying a distinct mechanism of substrate recognition. We further reveal distinct methylation kinetics and substrate preferences of DOT1A (H3K76me0) and DOT1B (DOT1A products H3K76me1/me2) in vitro, determined by a Ser and Ala residue within motif IV, respectively, enabling DOT1A and DOT1B to mediate efficient H3K76 tri-methylation non-processively but cooperatively, and suggesting why kinetoplastids have evolved two DOT1 enzymes.

Date: 2024
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DOI: 10.1038/s41467-024-46637-6

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