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Structure of DNMT3B homo-oligomer reveals vulnerability to impairment by ICF mutations

Author

Listed:
  • Linfeng Gao

    (University of California)

  • Yiran Guo

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill)

  • Mahamaya Biswal

    (University of California)

  • Jiuwei Lu

    (University of California)

  • Jiekai Yin

    (University of California)

  • Jian Fang

    (University of California)

  • Xinyi Chen

    (University of California)

  • Zengyu Shao

    (University of California)

  • Mengjiang Huang

    (University of California)

  • Yinsheng Wang

    (University of California
    University of California)

  • Gang Greg Wang

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine)

  • Jikui Song

    (University of California
    University of California)

Abstract

DNA methyltransferase DNMT3B plays an essential role in establishment of DNA methylation during embryogenesis. Mutations of DNMT3B are associated with human diseases, notably the immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome. How ICF mutations affect DNMT3B activity is not fully understood. Here we report the homo-oligomeric structure of DNMT3B methyltransferase domain, providing insight into DNMT3B-mediated DNA methylation in embryonic stem cells where the functional regulator DNMT3L is dispensable. The interplay between one of the oligomer interfaces (FF interface) and the catalytic loop renders DNMT3B homo-oligomer a conformation and activity distinct from the DNMT3B-DNMT3L heterotetramer, and a greater vulnerability to certain ICF mutations. Biochemical and cellular analyses further reveal that the ICF mutations of FF interface impair the DNA binding and heterochromatin targeting of DNMT3B, leading to reduced DNA methylation in cells. Together, this study provides a mechanistic understanding of DNMT3B-mediated DNA methylation and its dysregulation in disease.

Suggested Citation

  • Linfeng Gao & Yiran Guo & Mahamaya Biswal & Jiuwei Lu & Jiekai Yin & Jian Fang & Xinyi Chen & Zengyu Shao & Mengjiang Huang & Yinsheng Wang & Gang Greg Wang & Jikui Song, 2022. "Structure of DNMT3B homo-oligomer reveals vulnerability to impairment by ICF mutations," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31933-w
    DOI: 10.1038/s41467-022-31933-w
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    References listed on IDEAS

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    1. Jiuwei Lu & Yiran Guo & Jiekai Yin & Jianbin Chen & Yinsheng Wang & Gang Greg Wang & Jikui Song, 2024. "Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. 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.

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