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Cited by 26CRISPR and Genetic EngineeringBacterial Genetics and BiotechnologyBacteriophages and microbial interactions

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DdmDE eliminates plasmid invasion by DNA-guided DNA targeting

Open access
Yang, Xiao-Yuan, Shen, Zhangfei, Wang, Chen, Nakanishi, Kotaro, Fu, Tian-Min·2024·Cell
DOI 10.1016/j.cell.2024.07.028PMC PMC11995459

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Abstract

Horizontal gene transfer is a key driver of bacterial evolution, but it also presents severe risks to bacteria by introducing invasive mobile genetic elements. To counter these threats, bacteria have developed various defense systems, including prokaryotic Argonautes (pAgos) and the DNA defense module DdmDE system. Through biochemical analysis, structural determination, and in vivo plasmid clearance assays, we elucidate the assembly and activation mechanisms of DdmDE, which eliminates small, multicopy plasmids. We demonstrate that DdmE, a pAgo-like protein, acts as a catalytically inactive, DNA-guided, DNA-targeting defense module. In the presence of guide DNA, DdmE targets plasmids and recruits a dimeric DdmD, which contains nuclease and helicase domains. Upon binding to DNA substrates, DdmD transitions from an autoinhibited dimer to an active monomer, which then translocates along and cleaves the plasmids. Together, our findings reveal the intricate mechanisms underlying DdmDE-mediated plasmid clearance, offering fundamental insights into bacterial defense systems against plasmid invasions.

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Metadata

Authors
Yang, X.-Y., Shen, Z., Wang, C., Nakanishi, K., & Fu, T.-M.
Affiliations
  • The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
  • The Ohio State University (US)
Corresponding author
Fu, Tian-Min
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2024-09
Volume
187
Issue
19
Pages
5253-5266.e16
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2024.07.028
PMC
PMC11995459
OpenAlex
W4401757207
Cited by
26
References
3
Citations by year
2026: 10 · 2025: 14 · 2024: 2
FWCI
3.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institutes of Health (R01GM124320, R01GM138997)
  • École Polytechnique Fédérale de Lausanne
  • Ohio State University
  • National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Immunology and Microbiology › Virology › Bacteriophages and microbial interactions
Keywords
prokaryotic Argonaute, autoinhibition, horizontal gene transfer, mobile genetic elements, bacterial defense mechanisms

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