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Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2

Author

Listed:
  • Neil Justin

    (The Francis Crick Institute, Mill Hill Laboratory)

  • Ying Zhang

    (The Francis Crick Institute, Mill Hill Laboratory)

  • Cataldo Tarricone

    (The Francis Crick Institute, Mill Hill Laboratory)

  • Stephen R. Martin

    (Structural Biology Science Technology Platform, Francis Crick Institute, Mill Hill Laboratory)

  • Shuyang Chen

    (The Francis Crick Institute, Mill Hill Laboratory)

  • Elizabeth Underwood

    (The Francis Crick Institute, Mill Hill Laboratory)

  • Valeria De Marco

    (The Francis Crick Institute, Mill Hill Laboratory)

  • Lesley F. Haire

    (The Francis Crick Institute, Mill Hill Laboratory
    Structural Biology Science Technology Platform, Francis Crick Institute, Mill Hill Laboratory)

  • Philip A. Walker

    (Structural Biology Science Technology Platform, Francis Crick Institute, Mill Hill Laboratory)

  • Danny Reinberg

    (New York University School of Medicine)

  • Jon R. Wilson

    (The Francis Crick Institute, Mill Hill Laboratory)

  • Steven J. Gamblin

    (The Francis Crick Institute, Mill Hill Laboratory)

Abstract

Polycomb repressive complex 2 (PRC2) silences gene expression through trimethylation of K27 of histone H3 (H3K27me3) via its catalytic SET domain. A missense mutation in the substrate of PRC2, histone H3K27M, is associated with certain pediatric brain cancers and is linked to a global decrease of H3K27me3 in the affected cells thought to be mediated by inhibition of PRC2 activity. We present here the crystal structure of human PRC2 in complex with the inhibitory H3K27M peptide bound to the active site of the SET domain, with the methionine residue located in the pocket that normally accommodates the target lysine residue. The structure and binding studies suggest a mechanism for the oncogenic inhibition of H3K27M. The structure also reveals how binding of repressive marks, like H3K27me3, to the EED subunit of the complex leads to enhancement of the catalytic efficiency of the SET domain and thus the propagation of this repressive histone modification.

Suggested Citation

  • Neil Justin & Ying Zhang & Cataldo Tarricone & Stephen R. Martin & Shuyang Chen & Elizabeth Underwood & Valeria De Marco & Lesley F. Haire & Philip A. Walker & Danny Reinberg & Jon R. Wilson & Steven , 2016. "Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11316
    DOI: 10.1038/ncomms11316
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    Cited by:

    1. Carolina Gracia-Diaz & Yijing Zhou & Qian Yang & Reza Maroofian & Paula Espana-Bonilla & Chul-Hwan Lee & Shuo Zhang & Natàlia Padilla & Raquel Fueyo & Elisa A. Waxman & Sunyimeng Lei & Garrett Otrimsk, 2023. "Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Lihu Gong & Xiuli Liu & Lianying Jiao & Xin Yang & Andrew Lemoff & Xin Liu, 2022. "CK2-mediated phosphorylation of SUZ12 promotes PRC2 function by stabilizing enzyme active site," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Sara Weirich & Albert Jeltsch, 2023. "Limited choice of natural amino acids as mimetics restricts design of protein lysine methylation studies," Nature Communications, Nature, vol. 14(1), pages 1-3, December.

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