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Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation

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  • Hiwot Anteneh

    (University of California)

  • Jian Fang

    (University of California)

  • Jikui Song

    (University of California)

Abstract

DNA methyltransferase DNMT3A is essential for establishment of mammalian DNA methylation during development. The R882H DNMT3A is a hotspot mutation in acute myeloid leukemia (AML) causing aberrant DNA methylation. However, how this mutation affects the structure and function of DNMT3A remains unclear. Here we report structural characterization of wild-type and R882H-mutated DNMT3A in complex with DNA substrates with different sequence contexts. A loop from the target recognition domain (TRD loop) recognizes the CpG dinucleotides in a +1 flanking site-dependent manner. The R882H mutation reduces the DNA binding at the homodimeric interface, as well as the molecular link between the homodimeric interface and TRD loop, leading to enhanced dynamics of TRD loop. Consistently, in vitro methylation analyses indicate that the R882H mutation compromises the enzymatic activity, CpG specificity and flanking sequence preference of DNMT3A. Together, this study uncovers multiple defects of DNMT3A caused by the R882H mutation in AML.

Suggested Citation

  • Hiwot Anteneh & Jian Fang & Jikui Song, 2020. "Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16213-9
    DOI: 10.1038/s41467-020-16213-9
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    Cited by:

    1. 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.
    2. Zengyu Shao & Jiuwei Lu & Nelli Khudaverdyan & Jikui Song, 2024. "Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Jian Fang & Jianjun Jiang & Sarah M. Leichter & Jie Liu & Mahamaya Biswal & Nelli Khudaverdyan & Xuehua Zhong & Jikui Song, 2022. "Mechanistic basis for maintenance of CHG DNA methylation in plants," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. 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.
    5. 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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