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DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation

Author

Listed:
  • Sabrina Adam

    (University of Stuttgart)

  • Hiwot Anteneh

    (University of California)

  • Maximilian Hornisch

    (University of Stuttgart)

  • Vincent Wagner

    (University of Stuttgart)

  • Jiuwei Lu

    (University of California)

  • Nicole E. Radde

    (University of Stuttgart)

  • Pavel Bashtrykov

    (University of Stuttgart)

  • Jikui Song

    (University of California)

  • Albert Jeltsch

    (University of Stuttgart)

Abstract

DNA methylation maintenance by DNMT1 is an essential process in mammals but molecular mechanisms connecting DNA methylation patterns and enzyme activity remain elusive. Here, we systematically analyzed the specificity of DNMT1, revealing a pronounced influence of the DNA sequences flanking the target CpG site on DNMT1 activity. We determined DNMT1 structures in complex with preferred DNA substrates revealing that DNMT1 employs flanking sequence-dependent base flipping mechanisms, with large structural rearrangements of the DNA correlating with low catalytic activity. Moreover, flanking sequences influence the conformational dynamics of the active site and cofactor binding pocket. Importantly, we show that the flanking sequence preferences of DNMT1 highly correlate with genomic methylation in human and mouse cells, and 5-azacytidine triggered DNA demethylation is more pronounced at CpG sites with flanks disfavored by DNMT1. Overall, our findings uncover the intricate interplay between CpG-flanking sequence, DNMT1-mediated base flipping and the dynamic landscape of DNA methylation.

Suggested Citation

  • Sabrina Adam & Hiwot Anteneh & Maximilian Hornisch & Vincent Wagner & Jiuwei Lu & Nicole E. Radde & Pavel Bashtrykov & Jikui Song & Albert Jeltsch, 2020. "DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17531-8
    DOI: 10.1038/s41467-020-17531-8
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    Cited by:

    1. Pedro Weickert & Hao-Yi Li & Maximilian J. Götz & Sophie Dürauer & Denitsa Yaneva & Shubo Zhao & Jacqueline Cordes & Aleida C. Acampora & Ignasi Forne & Axel Imhof & Julian Stingele, 2023. "SPRTN patient variants cause global-genome DNA-protein crosslink repair defects," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Kosuke Yamaguchi & Xiaoying Chen & Brianna Rodgers & Fumihito Miura & Pavel Bashtrykov & Frédéric Bonhomme & Catalina Salinas-Luypaert & Deis Haxholli & Nicole Gutekunst & Bihter Özdemir Aygenli & Lau, 2024. "Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Vincent Wagner & Nicole Erika Radde, 2021. "SiCaSMA: An Alternative Stochastic Description via Concatenation of Markov Processes for a Class of Catalytic Systems," Mathematics, MDPI, vol. 9(10), pages 1-13, May.

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