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H2B Lys34 Ubiquitination Induces Nucleosome Distortion to Stimulate Dot1L Activity

Abstract

Ubiquitination-dependent histone crosstalk plays critical roles in chromatin-associated processes and is highly associated with human diseases. Mechanism studies of the crosstalk have been of the central focus. Here our study on the crosstalk between H2BK34ub and Dot1L-catalyzed H3K79me suggests a novel mechanism of ubiquitination-induced nucleosome distortion to stimulate the activity of an enzyme. We determined the cryo-electron microscopy structures of Dot1L–H2BK34ub nucleosome complex and the H2BK34ub nucleosome alone. The structures reveal that H2BK34ub induces an almost identical orientation and binding pattern of Dot1L on nucleosome as H2BK120ub, which positions Dot1L for the productive conformation through direct ubiquitin–enzyme contacts. However, H2BK34-anchored ubiquitin does not directly interact with Dot1L as occurs in the case of H2BK120ub, but rather induces DNA and histone distortion around the modified site. Our findings establish the structural framework for understanding the H2BK34ub–H3K79me trans-crosstalk and highlight the diversity of mechanisms for histone ubiquitination to activate chromatin-modifying enzymes.

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Fig. 1: Chemically ubiquitinated histone H2BK34ub stimulates Dot1L-mediated H3K79 methylation.
Fig. 2: H2BK34ub induces a similar orientation and interaction pattern of Dot1L as H2BK120ub.
Fig. 3: The effect of H2BK34ub on nucleosome structure and Dot1L activation.
Fig. 4: Dot1L methyltransferase activities on the variant modified nucleosomes obtained by chemical synthesis.

Data availability

The 1:1 and 2:1 maps of the Dot1L–H2BK34ub-H3K79Nle complex have been deposited in the EMDB with accession codes EMD-33126 and EMD-33127, and the atomic models in the Protein Data Bank under accession codes PDB 7XCR and 7XCT, respectively. The Dot1L–H2BK34ub-H3K79Nle complex map containing the additional Dot1L density (C-tail) was deposited in the EMDB under accession codes EMD-33128. The maps of unmodified nucleosome were deposited in the EMDB under accession codes EMD-33132 and the PDB under accession number 7XD1. The maps of native H2BK34ub nucleosome were deposited in the EMDB under accession codes EMD-33131 and the PDB under accession number 7XD0. The maps of Dot1L–H3K79Nleactive complex and Dot1L–H3K79Nleinactive were deposited in the EMDB under accession codes EMD-33139 and EMD-33141. The raw electron microscopy data are available on request. Source data are provided with this paper.

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Acknowledgements

We acknowledge the Tsinghua University Branch of China National Center for Protein Sciences Beijing for cryo-EM sample screening in 200 kV Arctica Tecnai microscopy and cryo-EM data collection in 300 kV TitanKiros microscopy. We thank X. Tian and H. Deng in the Center of Protein Analysis Technology, Tsinghua University, for HDX-MS analysis. We also thank Hefei KS-V Peptide Biological Technology Co. Ltd. for providing synthetic peptides (or proteins). This study was supported by the National Key R&D Program of China (2017YFA0505200), the National Natural Science Foundation of China (21977090, 32122024, 22137005, 91753205 and 81621002). Q.Q. was supported by the fund of National Facility for Translational Medicine (Shanghai).

Author information

Authors and Affiliations

Authors

Contributions

L. Liu, H.A., Z. Lou, & J.-B.L. proposed the idea and designed the experiments. H.A. expressed the Dot1L protein, reconstituted the nucleosomes, tested the ubiquitin-replacement activity experiments, performed the maleimide foot-printing essay, and determined the cryo-EM structures of unmodified nucleosome, H2BK34ub nucleosomes, and Dot1L–H3K79Nle nucleosome complex. A.L. performed the cryo-EM structure determination of the Dot1L–H2BK34ub-H3K79Nle nucleosome complex. M.S. expressed Dot1L mutant proteins, reconstituted the nucleosomes, and conducted the methyltransferase activity. Z.S. made the cryo-EM sample and participated in the cryo-EM data collection. Q.Q. synthesized H2BK34ub histone and PTMs histone variants, and assisted with the activity test. T.L. and S.Z. performed the MD simulation and analyzed the results. M.S., X.T. and H.D. performed the HDX-MS analysis. Z.Li performed the clones of Dot1L mutant plasmids. H.A., J.-B.L., Z. Lou, and L. Liu analyzed all data and wrote the manuscript. All authors read and discussed the manuscript.

Corresponding authors

Correspondence to Jia-Bin Li, Zhiyong Lou or Lei Liu.

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Nature Chemical Biology thanks Mehmet Öztürk and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Biochemical characterization of the Dot1L-H2BK34ub system.

a-c, Reconstitution of the unmodified (WT), H2BK34ub and H2BK120ub octamer, the size exclusion chromatography (SEC) spectrograms are shown with 15% SDS-PAGE analysis, respectively. d, Purification of Dot1L(1-416). e, DEAE column-based ion-exchange chromatography of the H2BK34ub nucleosome. f, SYBR Gold-stained 4.5% native gels of fractions in e. peak1: canonical H2BK34ub octasome, peak2: H2BK34ub hexasome. g, Methyltransferase activities of Dot1L(1-416) on the unmodified (WT) nucleosome, H2BK34ub hexasome and H2BK34ub ocatsome. h, ESI-MS spectrum and deconvoluted ESI-MS (average isotope) spectrum of histone H3K79Nle with an observed mass of 15255.3 Da (calculated 15257.9 Da). i, j, Superose 6 Increase column-based SEC purification and 4-12% SDS-PAGE analysis of the Dot1L-H2BK34ub complex after glutaraldehyde crosslinking.

Source data

Extended Data Fig. 2 Cryo-EM processing of the Dot1L-H2BK34ub complex.

a, The workflow of cryo-EM data processing of Dot1L-H2BK34ub complex in cryoSPARC. b-d, Local and overall resolution representation of the different complex map. The resolution was determined by the Fourier shell correlation FSC = 0.143 criterion.

Extended Data Fig. 3 Detail analysis of the Dot1L-H2BK34ub complex structure.

a, Different view of the 1:1 cryo-EM structure of Dot1L(1-416) bound to the H2BK34ub nucleosome, which contains a string of densities extended from the C terminal of Dot1L(4-332) to the DNA. b, Representative cryo-EM densities of histone H2A/H2B/H3/H4, Dot1L, DNA and ubiquitin. c, Molecular interaction of H2BK120ub and Dot1L. Mutations (I290A, L322A and F326A) that are important for the H2BK120ub nucleosome did not impair the activation of Dot1L by the H2BK34ub nucleosome. Data are presented as mean values ± SD for three biological replicates. d, Close-up view of the interaction between Dot1L and nucleosome. And the methyltransferase activity of WT and different mutant Dot1L constructs. Data are presented as mean values ± SD for three biological replicates.

Extended Data Fig. 4 Cryo-EM processing of the Dot1L-H3K79Nle complex.

The data was processed in RELION 3.1 softaware, the local resolution of the two final maps was estimated in Resmap software as colored in red to bule from 2.5 Å to 5.0 Å. The globular resolution of Dot1L-H3K79Nleactive was at 3.06 Å according to FSC (0.143) criterion, and the globular resolution of Dot1L-H3K79Nleinactive was at 3.27 Å. The Dot1L in Dot1L-H3K79Nleinactive complex was relatively flexible and lower resolution compared to nucleosome core parts, and it that can be further classified into three different Dot1L orientations (3.90 Å, 4.53 Å and 4.39 Å).

Extended Data Fig. 5 Structure alignments of different Dot1L-nucleosome complex.

a, Alignment of two different Dot1L-H3K79Nle complex maps. The Dot1L orientation in the nucleosomal surface varies. Left, the map representation, right, the cartoon representation. The movement distance and rotation angle were marked. b, Alignment of three maps of Dot1L-H2BK34ub-H3K79Nle complex. The Dot1L in the three maps shares the same orientation.

Extended Data Fig. 6 Cryo-EM processing of the unmodified nucleosome.

a, The workflow of cryo-EM data processing of the unmodified (WT) nucleosome in RELION version3.1. b, Local resolution representation of the unmodified nucleosome map calculated in the ResMap software. c, Fourier shell correlation (FSC) curve of the unmasked and masked map after postprocessing. The resolution was determined at the criterion of FSC 0.143. d, The angle distribution of the Euler sphere.

Extended Data Fig. 7 Cryo-EM processing of native H2BK34ub nucleosome.

a, The workflow of cryo-EM data processing of the H2BK34ub nucleosome in RELION. b, The angle distribution of the Euler sphere. c, FSC curve of the unmasked and masked map after postprocessing. The resolution was determined at the criterion of FSC 0.143. d, Local resolution representation of the unmodified nucleosome map calculated in the ResMap software. e, Four different conformations of H2BK34ub nucleosome varying in the unwrapping level of DNA SHL7 as marked in red dashed cycle.

Extended Data Fig. 8 Influence of H2BK34ub modification on nucleosomal H3K79 by Molecular Dynamics.

a, Histone H3 alignments of central structures from clusters of H2BK34ub-nucleosome (MD model, pinks and browns), H2BK34ub nucleosome (cryo-EM structure, magenta), and Dot1L-H2BK34ub nucleosome complex (cryo-EM structure, yellow). b, Plot of the cluster ID with the molecular dynamics simulation time of H2BK34ub-nucleosome model. c, Cluster proportion of H2BK34ub-nucleosome model within MD simulations. d, On the basis of a, the unmodified-nucleosome models (greys) and H2BK34ub-Dot1L complex models were aligned. The dark grey represents the cryo-EM structure of unmodified nucleosome. Light grey represents central structures from main clusters of unmodified-nucleosome model. Wheat represents the central structure from main cluster 1 of Dot1L-H2BK34ub complex MD model. e, Relative distance (Δdistance) changes of H3K79-H4E74 over MD simulation times. f, Conformational changes of H3K79-H4E74 with the alignments of H3 and H4 histones. The central structures from main clusters of unmodified-nucleosome model were in light greys, and the relevant cryo-EM structure was in dark grey. The central structures of H2BK34ub-nucleosome model were in pinks, and relevant cryo-EM structure was in magenta. The central structure from main cluster 1 of Dot1L-H2BK34ub complex model was in wheat, and the relevant cryo-EM structure was in yellow.

Extended Data Fig. 9 Influence of H2BK34ub modification on nucleosome structure and Dot1L stability by Molecular Dynamics.

a, RMSD of DNA GCT (−49~−47) motif from MD simulation models. The unmodified-nucleosome model was depicted as orange, and H2BK34ub-nucleosome model was depicted as blue. b, Distance changes of DT143-H3T45 over MD simulation time, unmodified-nucleosome model was colored as orange, and H2BK34ub-nucleosome was colored as blue. c, Distance representation of DT143-H3T45. DT143-H3T45 from the cryo-EM structure of unmodified nucleosome and the frame of H2BK34ub-nucleosome model at 400 ns were shown. d, Conformations of histones during MD simulations. e, Alignments of H3 and H4 histones. f, Interaction snapshot between H4 N-terminus and Dot1L. g, RMSD changes of Dot1L in Dot1L-H2BK34ub complex model over MD simulation time. h, RMS fluctuation (RMSF) of each Dot1L residue in Dot1L-H2BK34ub complex model over MD simulations. i, Dot1L stability representation relevant to h. Dot1L with larger fluctuation was in blue, and the relatively stable Dot1L was in orange.

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Ai, H., Sun, M., Liu, A. et al. H2B Lys34 Ubiquitination Induces Nucleosome Distortion to Stimulate Dot1L Activity. Nat Chem Biol (2022). https://doi.org/10.1038/s41589-022-01067-7

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