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

Frisbie, Victoria S.; Hashimoto, Hideharu; Xie, Yixuan; De Luna Vitorino, Francisca N.; Baeza, Josue; Nguyen, Tam; Yuan, Zhangerjiao; Kiselar, Janna; Garcia, Benjamin A.; Debler, Erik W.

doi:10.1038/s41467-024-46637-6

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

Journal Article · Tue Mar 19 00:00:00 EDT 2024 · Nature Communications

DOI:https://doi.org/10.1038/s41467-024-46637-6· OSTI ID:2470028

^[1]; Hashimoto, Hideharu ^[1]; ^[2]; ^[3]; Baeza, Josue ^[4]; Nguyen, Tam ^[1]; Yuan, Zhangerjiao ^[1]; Kiselar, Janna ^[5]; Garcia, Benjamin A. ^[2]; ^[1]

Thomas Jefferson University, Philadelphia, PA (United States)
Washington Univ., St. Louis, MO (United States). School of Medicine; Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine
Washington Univ., St. Louis, MO (United States). School of Medicine
Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine
Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL); Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357; AC02-76SF00515; SC0012704

OSTI ID:: 2470028

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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

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