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Molecular basis of foreign DNA recognition by BREX anti-phage immunity system

Author

Listed:
  • Alena Drobiazko

    (Skolkovo Institute of Science and Technology)

  • Myfanwy C. Adams

    (John Innes Centre)

  • Mikhail Skutel

    (Skolkovo Institute of Science and Technology)

  • Kristina Potekhina

    (Skolkovo Institute of Science and Technology)

  • Oksana Kotovskaya

    (Skolkovo Institute of Science and Technology)

  • Anna Trofimova

    (Skolkovo Institute of Science and Technology
    Russian Academy of Sciences)

  • Mikhail Matlashov

    (Skolkovo Institute of Science and Technology)

  • Daria Yatselenko

    (Skolkovo Institute of Science and Technology)

  • Karen L. Maxwell

    (University of Toronto)

  • Tim R. Blower

    (Durham University)

  • Konstantin Severinov

    (Russian Academy of Sciences
    Waksman Institute of Microbiology)

  • Dmitry Ghilarov

    (John Innes Centre)

  • Artem Isaev

    (Skolkovo Institute of Science and Technology)

Abstract

Anti-phage systems of the BREX (BacteRiophage EXclusion) superfamily rely on site-specific epigenetic DNA methylation to discriminate between the host and invading DNA. We demonstrate that in Type I BREX systems, defense and methylation require BREX site DNA binding by the BrxX (PglX) methyltransferase employing S-adenosyl methionine as a cofactor. We determined 2.2-Å cryoEM structure of Escherichia coli BrxX bound to target dsDNA revealing molecular details of BREX DNA recognition. Structure-guided engineering of BrxX expands its DNA specificity and dramatically enhances phage defense. We show that BrxX alone does not methylate DNA, and BREX activity requires an assembly of a supramolecular BrxBCXZ immune complex. Finally, we present a cryoEM structure of BrxX bound to a phage-encoded inhibitor Ocr that sequesters BrxX in an inactive dimeric form. We propose that BrxX-mediated foreign DNA sensing is a necessary first step in activation of BREX defense.

Suggested Citation

  • Alena Drobiazko & Myfanwy C. Adams & Mikhail Skutel & Kristina Potekhina & Oksana Kotovskaya & Anna Trofimova & Mikhail Matlashov & Daria Yatselenko & Karen L. Maxwell & Tim R. Blower & Konstantin Sev, 2025. "Molecular basis of foreign DNA recognition by BREX anti-phage immunity system," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57006-2
    DOI: 10.1038/s41467-025-57006-2
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    References listed on IDEAS

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