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Structural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction

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  • Xinyi Chen

    (University of California)

  • Yiran Guo

    (Duke University School of Medicine
    Duke University School of Medicine)

  • Ting Zhao

    (University of California)

  • Jiuwei Lu

    (University of California)

  • Jian Fang

    (University of California)

  • Yinsheng Wang

    (University of California
    University of California)

  • Gang Greg Wang

    (Duke University School of Medicine
    Duke University School of Medicine
    Duke University School of Medicine)

  • Jikui Song

    (University of California)

Abstract

Isoform 1 of DNA methyltransferase DNMT3A (DNMT3A1) specifically recognizes nucleosome monoubiquitylated at histone H2A lysine-119 (H2AK119ub1) for establishment of DNA methylation. Mis-regulation of this process may cause aberrant DNA methylation and pathogenesis. However, the molecular basis underlying DNMT3A1−nucleosome interaction remains elusive. Here we report the cryo-EM structure of DNMT3A1’s ubiquitin-dependent recruitment (UDR) fragment complexed with H2AK119ub1-modified nucleosome. DNMT3A1 UDR occupies an extensive nucleosome surface, involving the H2A-H2B acidic patch, a surface groove formed by H2A and H3, nucleosomal DNA, and H2AK119ub1. The DNMT3A1 UDR’s interaction with H2AK119ub1 affects the functionality of DNMT3A1 in cells in a context-dependent manner. Our structural and biochemical analysis also reveals competition between DNMT3A1 and JARID2, a cofactor of polycomb repression complex 2 (PRC2), for nucleosome binding, suggesting the interplay between different epigenetic pathways. Together, this study reports a molecular basis for H2AK119ub1-dependent DNMT3A1−nucleosome association, with important implications in DNMT3A1-mediated DNA methylation in development.

Suggested Citation

  • Xinyi Chen & Yiran Guo & Ting Zhao & Jiuwei Lu & Jian Fang & Yinsheng Wang & Gang Greg Wang & Jikui Song, 2024. "Structural basis for the H2AK119ub1-specific DNMT3A-nucleosome interaction," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50526-3
    DOI: 10.1038/s41467-024-50526-3
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