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

Author

Listed:
  • Victoria S. Frisbie

    (Thomas Jefferson University)

  • Hideharu Hashimoto

    (Thomas Jefferson University)

  • Yixuan Xie

    (Washington University School of Medicine
    Perelman School of Medicine at the University of Pennsylvania)

  • 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
    Perelman School of Medicine at the University of Pennsylvania)

  • Erik W. Debler

    (Thomas Jefferson University)

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.

Suggested Citation

  • Victoria S. Frisbie & Hideharu Hashimoto & Yixuan Xie & Francisca N. De Luna Vitorino & Josue Baeza & Tam Nguyen & Zhangerjiao Yuan & Janna Kiselar & Benjamin A. Garcia & Erik W. Debler, 2024. "Two DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46637-6
    DOI: 10.1038/s41467-024-46637-6
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