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

Journal article

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

Authors: Drobiazko, A; Adams, MC; Skutel, M; Potekhina, K; Kotovskaya, O

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 16
• Issue: 1
• Pages: 1825-1825
• Publication date: 2025-02-20
• DOI: 10.1038/s41467-025-57006-2
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Methyltransferase; Molecular biology; Bacteriophage; Epigenetics; DNA; Genetics; Escherichia coli; Gene; Gene expression; DNA methylation; Computational biology; Biology; DNA methyltransferase; Methylation